JP2021530462A - Formulation of anhydrous sodium thiosulfate - Google Patents

Abstract

Anhydrous sodium thiosulfate, a method for synthesizing the anhydrous sodium thiosulfate, a pharmaceutical composition thereof, and a method for treating ototoxicity are described herein. Anhydrous sodium thiosulfate is synthesized from sodium sulfite, sulfur, and cetylpyridinium chloride. Anhydrous sodium thiosulfate is formulated into a pharmaceutical composition comprising a buffer and a solvent. These compositions are useful in eliminating or reducing ototoxicity in pediatric patients receiving platinum-based chemotherapy. [Selection diagram] Fig. 6

Description

Cross-reference to related applications This application claims the priority of US Provisional Patent Applications Nos. 62 / 693,502 and 62 / 693,503, both filed on July 3, 2018. The entire contents of this document are incorporated herein by reference. This application is related to US Patent Application No. 16 / 458,261 entitled "ANHYDROUS SODIUM THIOSULFATE AND FORMULATIONS THEREOF" filed on 1 July 2019. The entire contents of this document are incorporated herein by reference.

Methods for synthesizing anhydrous sodium thiosulfate, the anhydrous sodium thiosulfate, and pharmaceutical compositions thereof are described herein. These compositions are useful in eliminating or reducing ototoxicity in patients receiving platinum-based chemotherapy.

Platinum-based therapies are a crucial component of the treatment regimen used in a variety of pediatric malignancies such as neuroblastoma, hepatoblastoma, medulloblastoma, osteosarcoma, malignant germ cell tumors, and nasopharyngeal carcinoma. It is said that. At commonly used doses and schedules, platinum-based therapies such as cisplatin and carboplatin often cause progressive, bilateral, and irreversible, often with tinnitus. Deafness based on platinum chemotherapy is due to the death of extracochlear hair cells and can affect all hearing.

These toxicities can limit doses and are often clinically significant, especially in infants who are critically dependent on normal hearing for cognitive, psychosocial, and language development. The incidence of cisplatin-induced deafness in young children reaches about 40%, and in certain vulnerable groups the incidence is close to 100%. Even if the hearing loss in pediatrics is mild, its effects are substantial, with, among other things, language acquisition, learning, academic performance, social and emotional development, and poor quality of life. Therefore, there is a need for safe and effective pharmaceutical compositions and methods for treating pediatric patients and reducing ototoxicity and deafness in these patients without compromising the effectiveness of platinum-based therapies. ing.

One embodiment described herein is a pharmaceutical composition comprising sodium thiosulfate, one or more buffers, and a solvent. Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate. Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate. Another embodiment described herein is a pharmaceutical composition consisting essentially of anhydrous sodium thiosulfate. Another embodiment described herein is a pharmaceutical composition consisting essentially of aqueous anhydrous sodium thiosulfate.

Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate and one or more buffers. Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate and one or more buffers. In one aspect, the composition comprises from about 20 mg to 32 g anhydrous sodium thiosulfate. In another embodiment, the composition comprises about 98% by weight anhydrous sodium thiosulfate. In another embodiment, the composition is a dry powder. In another embodiment, the composition is a lyophilized solution.

Another embodiment described herein is a pharmaceutical composition comprising aqueous anhydrous sodium thiosulfate, one or more buffers, and a solvent. Another embodiment described herein is a pharmaceutical composition consisting essentially of anhydrous sodium thiosulfate, one or more buffers, and a solvent.

Another embodiment described herein is a pharmaceutical composition comprising about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate, one or more buffers from 0.001 M to about 0.5 M, and water. Is. Another embodiment described herein is a medicament comprising about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate, 0.01 M to about 0.5 M and pH 6.5 sodium phosphate, and water. It is a composition. Another embodiment described herein is with about 0.1M to about 2M aqueous anhydrous sodium thiosulfate and boric acid or salts thereof at 0.001M to about 0.5M and pH 8.6 to 8.8. , A pharmaceutical composition containing water. Another embodiment described herein is an aqueous anhydrous sodium thiosulfate of about 0.1 M to about 2 M and glycine or a salt thereof of 0.001 M to about 0.5 M and pH 8.5-8.9. It is a pharmaceutical composition containing water. Another embodiment described herein is aqueous anhydrous sodium thiosulfate of about 0.1 M to about 2 M and tris (hydroxymethyl) amino of 0.001 M to about 0.5 M and pH 8.5-8.9. A pharmaceutical composition containing methane (tromethane) or a salt thereof and water.

Another embodiment described herein is a pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. Another embodiment described herein is a pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and a pH of 8.6 to 8.8 boric acid or a salt thereof, and water. It is a thing. Another embodiment described herein is a medicament comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. It is a composition. Another embodiment described herein is aqueous anhydrous sodium thiosulfate of about 0.1 M to about 2 M and tris (hydroxymethyl) amino of 0.001 M to about 0.5 M and pH 8.5-8.9. A pharmaceutical composition containing methane (tromethane) or a salt thereof and water.

Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate, one or more buffers, and a solvent. In one aspect, the composition comprises from about 20 mg / mL to 320 mg / mL aqueous anhydrous sodium thiosulfate. In another embodiment, the composition comprises from about 8% to about 32% by weight aqueous anhydrous sodium thiosulfate. In another embodiment, the composition comprises from about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate. In another embodiment, the composition comprises one or more buffers ranging from about 0.001M to about 0.5M. In another embodiment, the one or more buffers are phosphate (phosphate), sulfate (sulfate), carbonate (carbonate), borate (borate), formalt (gelate), acetate (acetate), Propionate (propionate), butanoate (butanoate), lactate (milk salt), glycine, maleate (maleate), pyruvate (pyrvate), citrate (citrate), aconite (aconinate), Isocitrate (isocitrate), α-ketoglutarate (α-ketoglutarate), succinate (succinate), fumarate (fumarate), malate (apple salt), oxaloacetate (oxaloacetate), aspal Includes tate (aspartate), glutamate (glutamate), tris (hydroxymethyl) aminomethane (tromethamine), combinations thereof, or salts thereof. In another embodiment, the composition has a pH of about 5 to about 9.5. In another embodiment, the composition has a pH of about 6.5 or about 8.9. In another embodiment, the one or more buffers are borate or a salt thereof, glycine or a salt thereof, tris (hydroxymethyl) aminomethane (tromethamine) or a salt thereof, or phosphate or a salt thereof. Contains salt. In another embodiment, the one or more buffers comprises boric acid, glycine, tris (hydroxymethyl) aminomethane (tromethamine), or sodium phosphate. In another embodiment, the solvent comprises water. In another embodiment, the composition is sterile.

Another embodiment described herein is a pharmaceutical composition comprising from about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate and 0.001 M to about 0.5 M sodium phosphate or boric acid. .. In one aspect, the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M and pH 6.5 sodium phosphate. In another embodiment, the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.004 M and pH 8.6-8.8 borate or a salt thereof. In another embodiment, the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and glycine or a salt thereof at about 0.01 M to about 0.05 M and pH 8.5-8.9. In another embodiment, the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M and pH 8.5-8.9 tris (hydroxymethyl) aminomethane (tromethamine). Or with its salt.

Another embodiment described herein is a pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water.

Another embodiment described herein is a medicament comprising about 0.5 M aqueous anhydrous sodium thiosulfate, a borate or salt thereof at about 0.004 M and pH 8.6-8.8, and water. It is a composition.

Another embodiment described herein is about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 of glycine or a salt thereof, and water. It is a pharmaceutical composition containing.

Another embodiment described herein is about 0.5 M aqueous anhydrous sodium thiosulfate and tris (hydroxymethyl) aminomethane at about 0.01 M to about 0.05 M and pH 8.5-8.9. A pharmaceutical composition comprising tromethamine) or a salt thereof and water.

Another embodiment described herein is a method for preparing an anhydrous sodium thiosulfate-containing pharmaceutical formulation comprising combining anhydrous sodium sulfate with one or more buffers and solvents. In one aspect, the method further comprises filtering and sterilizing the pharmaceutical product. In another embodiment, the pharmaceutical product comprises from about 20 mg / mL to 320 mg / mL aqueous anhydrous sodium thiosulfate. In another embodiment, the pharmaceutical product comprises from about 8% by weight to about 32% by weight aqueous anhydrous sodium thiosulfate. In another embodiment, the present formulation comprises from about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate. In another embodiment, the present formulation comprises one or more buffers ranging from about 0.001M to about 0.5M. In another embodiment, the one or more buffers are phosphate, sulfate, carbonate, formate, acetate, propionate, butaneate, lactate, glycine, maleate, pyruvate, citrate. Acid salt, aconitate, isocitrate, α-ketoglutarate, succinate, fumarate, malate, oxaloacetate, asparagate, glutamate, tris (hydroxymethyl) aminomethane (tromethamine) , Their combination, or their salts. In another embodiment, the pharmaceutical product has a pH of about 5 to about 9.5. In another embodiment, the pharmaceutical product has a pH of about 6.5 or about 8.9. In another embodiment, the one or more buffers comprises borate or a salt thereof, glycine or a salt thereof, tris (hydroxymethyl) aminomethane (tromethamine) or a salt thereof, or a phosphate or a salt thereof. In another embodiment, the one or more buffers comprises sodium phosphate, glycine, or boric acid. In another embodiment, the solvent comprises water. In another embodiment, the pharmaceutical product comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. In another embodiment, the pharmaceutical product is prepared with about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M and pH 8.5-8.9 with tris (hydroxymethyl) aminomethane (tromethamine). , With water.

Another embodiment described herein is a method described herein comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. It is a pharmaceutical preparation manufactured by.

Another embodiment described herein comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. It is a pharmaceutical preparation produced by the method described.

Another embodiment described herein comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. It is a pharmaceutical preparation produced by the method described in the present specification.

Another embodiment described herein is about 0.5 M aqueous anhydrous sodium thiosulfate and tris (hydroxymethyl) aminomethane at about 0.01 M to about 0.05 M and pH 8.5-8.9. A pharmaceutical preparation produced by the method described herein, comprising (tromethamine) and water.

Another embodiment described herein is a means for preparing an anhydrous sodium thiosulfate-containing pharmaceutical formulation comprising combining anhydrous sodium sulfate with one or more buffers and solvents. Another embodiment is a pharmaceutical formulation prepared by the means described herein.

Another embodiment described herein is from about 0.2 M to about 2 M aqueous sodium thiosulfate solution, from about 0.001 M to about 0.05 M pharmaceutically acceptable buffer, and from about 0.005 M. A pharmaceutical composition comprising a pharmaceutically acceptable salt of about 0.05 M and a pH of about 5 to about 9.5.

Another embodiment described herein is a kit comprising an aqueous sodium thiosulfate formulation comprising one or more receptacles containing aqueous sodium thiosulfate and a document containing prescription information or instructions for use. Is. In one aspect, the kit further comprises one or more syringes, a subcutaneous injection needle, and a package.

Another embodiment described herein is one or more receptacles containing dried or lyophilized sodium thiosulfate and optionally one or more sterile solvents, needles and syringes suitable for reconstruction. And a document containing prescription information or instructions for use.

Another embodiment described herein is a pharmaceutical formulation comprising stable aqueous anhydrous sodium thiosulfate for injection that does not precipitate after sterilization and storage. In one aspect, the formulation comprises from about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate, 0.001 M to about 0.5 M sodium phosphate, glycine, tris (hydroxymethyl) aminomethane (tromethamine), or borate. Contains acid.

Another embodiment described herein is anhydrous sodium thiosulfate characterized by an X-ray powder diffraction (XRPD) pattern, collected from about 2 to about 40 ° 2θ using copper Kα radiation. In some cases, 10.52, 15.13, 17.71, 19.70, 21.09, 21.49, 21.84, 27.40, 28.96, 30.46, 31.81, 32.52. , 33.15, 37.40, or at least four peaks selected from 38.16 ° 2 theta (2θ) ± 0.2 are included in this XRPD pattern. In one aspect, anhydrous sodium thiosulfate is characterized by an X-ray powder diffraction (XRPD) pattern, when the XRPD is collected to about 2 to about 40 ° 2θ using copper Kα radiation. 10.52, 15.13, 19.70, 21.49, 21.84, 28.96, 30.46, 33.15, 37.40, and 38.16 ° 2 theta (2θ) ± 0.2 At least four peaks selected from are included in this XRPD pattern. In another embodiment, anhydrous sodium thiosulfate has a low melting initiation by differential scanning calorimetry of about 331 ° C and a minimal weight loss at ambient temperature to 162 ° C, as evidenced by thermogravimetric analysis. It is characterized in that the weight loss is 14.8% at 162 ° C to 309 ° C and the decomposition is started at 436 ° C.

Another embodiment described herein includes cadmium of 0.1 μg / g or less, lead of 0.25 μg / g or less, arsenic of 0.75 μg / g or less, and mercury of 0.15 μg / g or less. Cobalt of 0.25 μg / g or less, vanadium of 0.5 μg / g or less, nickel of 1.0 μg / g or less, lithium of 12.5 μg / g or less, antimony of 4.5 μg / g or less, Anhydrous comprising 15.0 μg / g or less of copper, 1500 ppm or less of methanol, 3% (w / w) or less of water, and 1.65% (w / w) of total impurities or related substances. It is sodium thiosulfate.

Another embodiment described herein is a method of synthesizing sodium thiosulfate, which comprises reacting sodium sulfite with sulfur in the presence of a surface agent. In one aspect, the surface agent comprises cetylpyridinium chloride. In another embodiment, the reaction is aqueous. In another embodiment, the reaction is carried out at about 80 ° C to about 100 ° C. In another embodiment, sodium thiosulfate is crystallized and then washed with acetone.

Another embodiment described herein is a method of synthesizing anhydrous sodium thiosulfate, which comprises reacting sodium sulfite with sulfur in the presence of cetylpyridinium chloride to dehydrate the sodium thiosulfate product. In one embodiment, the reaction comprises 1.0 molar equivalents of sodium sulfite, 1.1 molar equivalents of sulfur, and 0.00013 molar equivalents of cetylpyridinium chloride. In another embodiment, the reaction is aqueous. In another embodiment, the reaction is carried out at about 80 ° C to about 100 ° C. In another embodiment, sodium thiosulfate is crystallized and then washed with acetone. In another embodiment, sodium thiosulfate is dehydrated and washed with methanol. In another embodiment, the sodium thiosulfate is dried.

Another embodiment described herein is (a) reacting aqueous sodium sulfite with sulfur and cetylpyridinium chloride, (b) crystallizing sodium thiosulfate and washing with acetone, and ( c) A method for synthesizing anhydrous sodium thiosulfate, which comprises dehydrating the washed sodium thiosulfate with methanol and (d) drying the dehydrated sodium thiosulfate. In one embodiment, the reaction comprises 1.0 molar equivalents of sodium sulfite, 1.1 molar equivalents of sulfur, and 0.00013 molar equivalents of cetylpyridinium chloride.

Another embodiment described herein is (a) 1.0 mol equivalent of aqueous sodium thiosulfate at about 90 ° C to about 100 ° C in the presence of 0.00013 mol equivalent of cetylpyridinium chloride. Reacting with 1 molar equivalent of sulfur, (b) crystallizing sodium thiosulfate below 2 ° C. and washing with acetone, and (c) dehydrating the washed sodium thiosulfate with methanol. , (D) A method for synthesizing anhydrous sodium thiosulfate, which comprises drying dehydrated sodium thiosulfate to dehydrated sodium thiosulfate at about 25 ° C. to about 60 ° C.

Another embodiment described herein is anhydrous sodium thiosulfate synthesized by the methods described herein.

Another embodiment described herein is to react sodium sulfite with sulfur in the presence of cetylpyridinium chloride, to crystallize the sodium thiosulfate product, and to dehydrate the sodium thiosulfate product. It is a means for synthesizing anhydrous sodium thiosulfate, including.

Another embodiment described herein is anhydrous sodium thiosulfate synthesized by the means described herein.

Another embodiment described herein is anhydrous sodium thiosulfate, which is essentially free of sodium thiosulfate pentahydrate.

Another embodiment described herein is (a) mixing one or more proportions of sodium thiosulfate with a predetermined amount of cisplatin, (b) incubating the mixture for a period of time, and (c). ) A method for measuring the binding capacity of sodium thiosulfate to cisplatin, including analyzing the apparent concentration of cisplatin. In one aspect, the molar ratio of sodium thiosulfate to cisplatin comprises 10: 1 to 1: 1. In another aspect, the molar ratio of sodium thiosulfate to cisplatin comprises 10: 1, 6: 1 and 5: 1. In another aspect, the incubation time includes 1 minute to 180 minutes. In another aspect, the incubation time includes about 5 minutes, about 35 minutes, about 65 minutes and about 95 minutes. In another aspect, the analysis includes HPLC and UV detection.

Another embodiment described herein is for preventing or reducing the incidence of cisplatin (CIS) chemotherapy-induced ototoxicity in patients with localized non-metastatic solid tumors aged 1 month to <18 years. The method comprises injecting sodium thiosulfate for injection for 15 minutes 6 hours after the completion of each CIS administration if the CIS is infused within 6 hours.

Compositions and methods for reducing ototoxicity in patients receiving platinum-based chemotherapy are also described herein. In particular, compositions and intravenous formulations have been described for reducing ototoxicity in pediatric patients. It also describes methods for administering the compositions and formulations. The method comprises administering to the patient an effective amount of sodium thiosulfate following administration of a platinum-based chemotherapeutic agent. As described herein, administration of sodium thiosulfate reduces the incidence and severity of ototoxicity in pediatric patients without adversely affecting the effectiveness of platinum-based chemotherapeutic agents. Was found. In one aspect, the method comprises administering the sodium thiosulfate pharmaceutical composition described herein. In another embodiment, the pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. In another embodiment, the pharmaceutical product is prepared with about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M and pH 8.5-8.9 with tris (hydroxymethyl) aminomethane (tromethamine). , With water. Another embodiment is a method of reducing ototoxicity in a patient suffering from cancer and receiving platinum-based chemotherapy, the method comprising administering to the patient an effective amount of sodium thiosulfate.

Another embodiment is a method of prophylactically treating a patient suffering from cancer and receiving platinum-based chemotherapy to reduce the patient's chances of suffering from ototoxicity, the method of which is an effective amount of thiosulfate. Includes administration of sodium to the patient. In one aspect, the method comprises administering the sodium thiosulfate pharmaceutical composition described herein. In one aspect, the pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. In another embodiment, the pharmaceutical product is prepared with about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M and pH 8.5-8.9 with tris (hydroxymethyl) aminomethane (tromethamine). , With water.

Another embodiment is a method of reducing long-term ototoxicity in a patient suffering from cancer and receiving platinum-based chemotherapy, the method comprising administering to the patient an effective amount of sodium thiosulfate. In one aspect, the method comprises administering the sodium thiosulfate pharmaceutical composition described herein. In another embodiment, the pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. In another embodiment, the pharmaceutical product is prepared with about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M and pH 8.5-8.9 with tris (hydroxymethyl) aminomethane (tromethamine). , With water.

Another embodiment is a method of reducing the concentration of cisplatin in the ear cavity of a patient suffering from cancer and receiving platinum-based chemotherapy, in which an effective amount of sodium thiosulfate is administered to the patient. Including that. According to this method, the effect of platinum-based chemotherapeutic agent-induced ototoxicity on patients who receive sodium thiosulfate without substantially detecting cisplatin in the ear cavity is reduced.

Another embodiment is a method of inhibiting the ototoxic effect associated with administering a platinum-based chemotherapeutic compound to a patient, the method comprising administering to the patient an effective amount of sodium thiosulfate. ..

In some embodiments described herein, a patient who is a carrier has a single nucleotide polymorphism within the gene ACYP2 at locus rs1872328. In some embodiments, patients receiving sodium thiosulfate are about 20% to about 75% less likely to experience ototoxicity than patients not receiving sodium thiosulfate. In some embodiments, patients receiving sodium thiosulfate are about 50% less likely to experience ototoxicity than patients not receiving sodium thiosulfate. In some embodiments, ototoxicity includes deafness, imbalance, tinnitus, hyperacusis, or a combination thereof.

In some embodiments described herein, the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin. In some embodiments, the platinum-based chemotherapeutic agent is cisplatin.

In some embodiments, the cancer being treated is localized or disseminated. In some embodiments, the cancer being treated is localized. In some embodiments, the cancer being treated is selected from germ cell tumors, hepatoblastomas, medulloblastomas, neuroblastomas, and osteosarcomas. In some embodiments, the cancer being treated is hepatoblastoma. In some embodiments, the cancer being treated is a standard-risk cancer, a moderate-risk cancer, or a high-risk cancer. In some embodiments, the cancer being treated is a standard-risk cancer or a moderate-risk cancer. In some embodiments, the cancer being treated is standard-risk or moderate-risk hepatoblastoma.

In some embodiments, sodium thiosulfate is administered before, at the same time as, or after administration of the platinum-based chemotherapeutic agent. In some embodiments, sodium thiosulfate is administered about 0.5 to about 10 hours after administration of the platinum-based chemotherapeutic agent. In some embodiments, sodium thiosulfate is administered intravenously. In some embodiments, the effective amount of sodium thiosulfate is about per cycle platinum-based chemotherapeutic agent 5 g / m 2 ^~ about 25 g / m ^2. In some embodiments, the patient is treated with a dose of about 1 mg / kg to about 5 mg / kg or about 10 mg / m ² to about 300 mg / m ^{2 per cycle of platinum-based chemotherapeutic agent.} In one aspect, sodium thiosulfate comprises the pharmaceutical composition described herein. In another embodiment, the sodium thiosulfate pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. In another embodiment, the pharmaceutical product is prepared with about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M and pH 8.5-8.9 with tris (hydroxymethyl) aminomethane (tromethamine). , With water.

In some embodiments described herein, ototoxicity is tinnitus function index, block grading, American Speech-Language-Hearing Association criteria, or the International Society of Pediatric Oncology. Determined by one or more criteria, including the Boston Ototoxicity Scale (International Society of Speech Oncology Online). In some embodiments, ototoxicity measures deafness at one or more frequencies, including 500 Hz, 1,000 Hz, 2,000 Hz, 4,000 Hz, or 8,000 Hz, or a combination of those frequencies. Measured by. Hearing changes are then calculated relative to baseline measurements prior to the patient receiving platinum-based chemotherapy and / or sodium thiosulfate.

In some embodiments described herein, ototoxicity is calculated by one or more criteria, which are cited as: (a) measured by a loss of 20 dB at a single frequency. Deafness, (b) Deafness measured by loss of 10 dB at two consecutive frequencies, (c) Loss of response at three consecutive test frequencies for which a response was previously obtained, (d) Features below Reduction of bilateral high-frequency deafness with: (i) Deafness of less than 40 dB at all frequencies and showing grade 0 or minimal deafness, (ii) Deafness of 40 dB or more only at 8,000 Hz. Grade 1 or mild deafness, (iii) deafness of 40 dB or more at 4,000 Hz or higher, grade 2 or moderate deafness, (iv) 40 dB or higher at 2,000 Hz or higher Deafness with grade 3 or marked deafness, (v) deafness of 40 dB or more at 1,000 Hz or higher with grade 4 or severe deafness, or (e) the following features Deafness with: (i) Deafness of 20 dB or less at all frequencies and showing grade 0 deafness, (ii) HL of more than 4,000 Hz and more than 20 dB, grade 1 deafness Shown, (iii) HL over 20 dB at 4,000 Hz and above, showing grade 2 deafness, (iv) HL over 20 dB at 2,000 Hz or 3,000 Hz, grade 3. Deafness, (v) HL above 40 dB above 2,000 Hz, which indicates grade 1 deafness, or (f) improvement in ear ringing function index, where changes in hearing are present in the patient Is calculated by comparison with baseline measurements prior to administration of platinum-based chemotherapeutic agents and / or sodium thiosulfate. In some embodiments, pediatric patients receiving sodium thiosulfate have reduced ototoxicity as assessed by criterion (d) above as compared to pediatric patients not receiving sodium thiosulfate. ..

In some embodiments described herein, administration of sodium thiosulfate to a patient increases serum creatinine or glomerular filtration rate as compared to a patient not receiving sodium thiosulfate. It does not lead to a decline. In some embodiments, administration of sodium thiosulfate to a patient does not affect progression-free survival or overall survival as compared to a patient not receiving sodium thiosulfate. .. In some embodiments, even if sodium thiosulfate is administered to the patient, one or more adverse effects including febrile neutropenia, infection, hypomagnesemia, hypernatremia, vomiting, or nausea. The incidence of events does not increase.

In some embodiments described herein, ototoxicity is measured at least 4 weeks after administration of a platinum-based chemotherapeutic agent and sodium thiosulfate to a patient. In one aspect, sodium thiosulfate comprises the pharmaceutical composition described herein. In another embodiment, the sodium thiosulfate pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. In another embodiment, the pharmaceutical product is prepared with about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M and pH 8.5-8.9 with tris (hydroxymethyl) aminomethane (tromethamine). , With water.

In some embodiments described herein, the patient is a pediatric patient. In some embodiments described herein, pediatric patients are 1 week to 18 years of age. In some embodiments, the pediatric patient is about 12 years or younger. In some embodiments, the pediatric patient is about 5 years or younger. In some embodiments, the pediatric patient is about 2 years or younger. In some embodiments, the pediatric patient is about 1 year or younger.

Another embodiment is a dosing regimen for treating hepatoblastoma in pediatric patients, which dosing regimens include: (a) from about 1 mg / kg to about 5 mg / kg or about 10 mg / m ² to per cycle. Administering a dose of about 300 mg / m ² of cisplatin (b) Containing administration of about 5 g / m ² to about 25 g / m ² of sodium thiosulfate per cycle of cisplatin, sodium thiosulfate from administration of cisplatin Administered approximately 2 to approximately 6 hours later, this dosing regimen achieved reduced ototoxicity when administered to pediatric patients compared to sodium thiosulfate-free dosing regimens administered to pediatric patients. Ototoxicity: (a) Deafness measured by loss of 20 dB at a single frequency, (b) Deafness measured by loss of 10 dB at two consecutive frequencies, (c) Previous response Loss of response at 3 consecutive test frequencies obtained in, (d) Deafness characterized by the following criteria Decrease in bilateral high frequency deafness: (i) Deafness less than 40 dB at all frequencies, grade 0 Alternatively, those showing minimal deafness, (ii) deafness of 40 dB or more only at 8,000 Hz and grade 1 or mild deafness, (iii) deafness of 40 dB or more at 4,000 Hz or higher. , Grade 2 or moderate deafness, (iv) 40 dB or more deafness at 2,000 Hz or higher, and grade 3 or marked deafness, (v) 40 dB or higher at 1,000 Hz or higher Deafness of grade 4 or severe deafness, or (e) hearing loss characterized by the following criteria: (i) deafness of 20 dB or less at all frequencies, grade 0 (Ii) HL over 4,000 Hz and over 20 dB and grade 1 deafness, (iii) HL above 4,000 Hz and over 20 dB and grade 2 deafness (Iv) HL over 20 dB at 2,000 Hz or 3,000 Hz and showing grade 3 deafness, (v) HL over 40 dB at 2,000 Hz and above, this is grade 1. Deafness is indicated and changes in hearing are calculated compared to baseline measurements prior to the patient receiving platinum-based chemotherapeutic agent and / or sodium thiosulfate. Determined by one or more criteria selected. In one aspect, the regimen comprises administering the sodium thiosulfate pharmaceutical composition described herein. In another embodiment, the pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. In another embodiment, the pharmaceutical product is prepared with about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M and pH 8.5-8.9 with tris (hydroxymethyl) aminomethane (tromethamine). , With water.

Another embodiment has standard or moderate risk hepatoblastoma at about 12 years of age with doses of about 1 mg / kg to about 5 mg / kg or about 10 mg / m ^{2 to} about 300 mg / m ^2. A method of reducing ototoxicity in pediatric patients receiving this method, which administers approximately 5 g / m ² to approximately 25 g / m ² of sodium thiosulfate per cycle of cisplatin approximately 6 hours after administration of cisplatin. Including doing. In this method, one or more criteria for calculating deafness toxicity are as follows: (a) Deafness measured by a loss of 20 dB at a single frequency, (b) Loss of 10 dB at two consecutive frequencies. Deafness measured, (c) loss of response at three consecutive test frequencies for which a response was previously obtained, (d) loss of hearing characterized by the following criteria: reduction of bilateral high frequency deafness: (i) all Deafness less than 40 dB in frequency and showing grade 0 or minimal deafness, (ii) Deafness above 40 dB only at 8,000 Hz and showing grade 1 or mild deafness, (iii) Deafness of 40 dB or more at 4,000 Hz or higher and showing grade 2 or moderate deafness, (iv) Deafness of 40 dB or higher at 2,000 Hz or higher and showing grade 3 or marked deafness (V) Deafness of 40 dB or more at 1,000 Hz or higher and showing grade 4 or severe deafness, or (e) Deafness characterized by the following criteria: (i) All Deafness of 20 dB or less in frequency and showing grade 0 deafness, (ii) HL of more than 4,000 Hz and more than 20 dB and showing grade 1 deafness, (iii) of 4,000 Hz or more HL over 20 dB and showing grade 2 deafness, (iv) HL over 20 dB at 2,000 Hz or 3,000 Hz and showing grade 3 deafness, (v) 2, HL above 40 dB above 000 Hz, indicating grade 1 deafness, where changes in hearing are based before the patient is given platinum-based chemotherapeutic agents and / or sodium thiosulfate. Calculated in comparison to line measurements, and administration of sodium thiosulfate is substantially greater in progression-free survival or overall survival compared to pediatric patients not receiving sodium thiosulfate. And administration of sodium thiosulfate does not affect, and administration of sodium thiosulfate is one or more adverse events including febrile neutrophilia, infection, hypomagnesemia, hypernatremia, vomiting, or deafness. Is selected from those that do not substantially increase the incidence of. In one aspect, the method comprises administering the sodium thiosulfate pharmaceutical composition described herein. In another embodiment, the pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. In another embodiment, the present formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. In another embodiment, the pharmaceutical product is prepared with about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M and pH 8.5-8.9 with tris (hydroxymethyl) aminomethane (tromethamine). , With water.

One or more embodiments or embodiments may be incorporated in different embodiments or embodiments, but may not be specifically described. That is, all embodiments and embodiments may be used in any way or in combination.

FIG. 1 shows a scheme for synthesizing anhydrous sodium thiosulfate. FIG. 2A shows an X-ray powder diffraction pattern of anhydrous sodium thiosulfate synthesized as described herein. The peaks are as shown in Table 5. FIG. 2B shows an X-ray powder diffraction pattern of sodium thiosulfate pentahydrate. The peaks are as shown in Table 6. FIG. 3 shows an overlaid X-ray powder diffraction pattern for sodium thiosulfate pentahydrate (upper pattern) and anhydrous sodium thiosulfate (lower pattern) synthesized as described herein. FIG. 4A shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) overlaid for anhydrous sodium thiosulfate synthesized as described herein. The DSC thermogram shows that a rapid single endotherm started at 331.4 ° C. In thermogravimetric analysis, the weight loss was slight at 25 ° C. to 162 ° C., the weight loss was 14.81% at 162 ° C. to 309 ° C., and the decomposition was started at 436 ° C. thereafter. FIG. 4B shows the dynamic vapor sorption (DVS) isotherms of anhydrous sodium thiosulfate synthesized as described herein. Minimal weight changes were observed in the DVS isotherms when equilibrated to 0% relative humidity. When settled, a 165% weight increase is seen. Upon desorption, hysteresis was observed and a 51% weight loss was observed. FIG. 5 illustrates a cisplatin concentration-to-time plot in combination with cisplatin (control) or sodium thiosulfate with a sodium thiosulfate: cisplatin ratio of 5: 1, 6: 1 or 10: 1. It was done. The data are as shown in Table 7. FIG. 6 shows a scheme for preparing a pharmaceutical preparation containing anhydrous sodium thiosulfate.

As used herein, the terms "active ingredient," "pharmaceutical active ingredient," or "API" are agents, pharmaceutical active ingredients, compounds or substances, compositions that provide pharmacologically and often beneficial effects. Refers to a thing or a mixture thereof.

As used herein, the term "dose" means any form of active ingredient formulation comprising an amount sufficient to exert a therapeutic effect on a single dose.

As used herein, the term "dosage" refers to a particular amount, number, and frequency of administration over a particular period of time, usually a day.

As used herein, the term "pharmaceutical active ingredient loading" or "drug loading" refers to the amount (mass) of pharmaceutical active ingredient contained in a single soft capsule filling.

As used herein, the term "formulation" or "pharmaceutical composition" refers to a drug in combination with a pharmaceutically acceptable excipient.

As used herein, the term "particle size distribution" (PSD) refers to the average particle size according to the statistical distribution of the particle size range described herein. The distribution can be Gaussian, normal, or nonnormal.

Terms such as "d90", "d50", and "d10" refer to percentages of particle size (eg, 90%, 50%, or 10%, respectively) that are smaller than the specified size, range, or distribution. For example, “d90 ≦ 100 μm” means that 90% of the particles having a particle size within the distribution range are 100 μm or less.

As used herein, the term "patient" refers to any subject, including mammals and humans. Patients are being treated with drugs because they are suspected of having or are suspected of having the disease. In some examples, the patient is a mammal, such as a human, or their premature babies, newborns, infants, young people, adolescents or adults, non-human primates, dogs, cats, horses, cows, goats, pigs, rabbits. , Rats, mice. In some examples, the term "patient" as used herein refers to a human (eg, male, female, or infant). In some examples, the term "patient" as used herein refers to an experimental animal in an animal model study. The patient or subject can be of any age, gender, or a combination thereof. In some embodiments described herein, the patient is treated with a platinum-based chemotherapeutic agent such as cisplatin, followed by administration of sodium thiosulfate or a formulation thereof.

The term "pediatric patient" refers to a pediatric mammal or human. In some examples, the patient is a human or its premature baby, newborn, infant, toddler, toddler, adolescent, young or teenager, non-human primate, dog, cat, horse, cow, goat, pig, rabbit. , Rats, mice and other mammals. Pediatric patients can be of any ethnicity or gender. Pediatric patients can be of any age as understood by those skilled in the art to be pediatric patients in medicine and veterinary medicine. For example, a human pediatric patient can be a newborn up to 18 years of age. It is understood that newborns are one month old, infants are one to two years old, infants are two to twelve years old, and adolescents are twelve to eighteen years old. In some countries, pediatric patients include patients up to the age of 21. Pediatric patients are being treated with drugs because they are suspected of having or are suspected of having the disease. In some embodiments further described herein, the pediatric patient is treated with a platinum-based chemotherapeutic agent such as cisplatin.

The term "ototoxicity" refers to any type of toxicity that affects the ear. Toxicity can be to cochlear (eg, cochlear toxicity), cochlear hair cells, auditory nerve or vestibular system, or any of these systems found in the ear, or in combination with any of these systems. Toxicity can manifest as hearing loss, sensorineural hearing loss, imbalance, tinnitus or hyperacusis, or a combination thereof. When referred to for deafness, the amount of toxicity that causes deafness is mild, moderate, severe, severe, or total that results in complete deafness. Alternatively, hearing loss may be present at both high and low frequencies, as well as at certain frequencies, including all repetitions of frequencies normal to mammalian hearing. Toxicity can be unilateral, bilateral, bilateral symmetry, or bilateral asymmetry, with one ear being more affected than the other.

As used herein, the term "biological sample" or "sample" refers to a sample taken or derived from a patient. As an example, biological samples include body fluids, blood, whole blood, plasma, serum, mucous secretions, saliva, cerebrospinal fluid (CSF), bronchial alveolar lavage fluid (BALF), urine, ocular fluid (vitrous fluid, tufts). Includes materials selected from the group consisting of (such as water), lymph, lymph node tissue, spleen tissue, bone marrow, and auditory cavity.

The term "treat" refers to administering treatment in an amount, method, or mode (eg, therapeutic effect) that is effective in improving the condition, symptoms, disorder or parameter associated with the disorder, or their probability. Point to.

The term "prevention" refers to preventing or reducing the progression of a disorder to a statistically significant degree or to a extent detectable by one of ordinary skill in the art.

The terms "essentially" or "substantially" as used herein mean, to a large or significant extent, but are not complete.
As used herein, the term "about" is arbitrary, including both integer and decimal components within a range of up to ± 10% of the value modified by the term "about". Point to a value.

As described herein, sodium thiosulfate (STS) has been found to reduce ototoxicity in pediatric patients treated with platinum-based chemotherapeutic agents. A phenomenal discovery was made. Infants under the age of 12 have a higher rate of ototoxicity, and infants under the age of 5 are at even higher risk. A further finding is that administration of STS after platinum-based chemotherapeutic agents (such as cisplatin) significantly reduced ototoxicity in these pediatric patients. A specific finding is that STS may reduce the severity of ototoxicity, such as block grade 2 and 3 ototoxicity. Further identified was that the total or cumulative dose of cisplatin exposure did not interfere with STS-mediated ear protection. In addition, STS has also been found to be highly suitable as an ear protectant when used in connection with local (non-disseminated) cancers. See International Patent Application Publication No. WO 2019/108592, which is a continuation of US Patent Application No. 15 / 286,243 filed on November 29, 2017. The entire contents of both documents are incorporated herein by reference.

Sodium thiosulfate (also known as sodium hyposulfite) is a water-soluble thiol compound of _{the formula Na 2} S ₂ O _3. The compounds are available in anhydrous and crystalline form. The most common hydrate form is the pentahydrate crystalline form. STS is commercially available as an established antidote to acute cyanide poisoning. STS is a reducing agent and has been used in oncology as an antidote for extravasation of various chemotherapeutic agents for the purpose of preventing cisplatin nephrotoxicity and carboplatin ototoxicity. The mechanism by which sodium thiosulfate reduces cisplatin-induced nephrotoxicity and carboplatin-induced ototoxicity is not understood. The proposed mechanism of action includes its thiol group. This thiol group allows it to act as a free radical scavenger and / or by covalent binding and inactivation of the platinum compound. Sodium thiosulfate reacts irreversibly with cisplatin to form Pt (S ₂ O ₃ ) ₄ when the drug is administered simultaneously, sequentially, or nearly simultaneously. Sodium thiosulfate is also thought to protect against nephrotoxicity by reducing the delivery of cisplatin to the kidneys and neutralizing cisplatin in kidneys with high concentrations of sodium thiosulfate. After intravenous administration, sodium thiosulfate is dispersed throughout the extracellular fluid. Some sodium thiosulfate is converted to sulphate in the liver and up to 95% is excreted untreated in the urine. The biological half-life is 0.65 hours (range: varies from 16.5 to 182 minutes depending on dose). When administered intravenously, STS is rapidly excreted from the kidney.

Without being bound by any theory, the biological effects of STS in the prevention of cisplatin-induced ototoxicity include binding to electrophilic platinum molecules, removal of reactive oxygen species, and intracochlear endolymph. It is believed that increased concentrations are included. Therefore, an effective single dose removes the residual platinum chemotherapeutic agent so that the cochlear hair does not accumulate and be damaged. The effectiveness of cisplatin-based chemotherapy in pediatric patients was unaffected when STS was administered, as evidenced by the results of two Phase III clinical trials.

In addition, STS does not adversely affect the efficacy of some other non-platinum-based chemotherapeutic agents, such as doxorubicin and etoposide. In vitro studies of small cell lung cancer cell cultures showed no reduction in etoposide cytotoxicity after 72 hours of incubation after immediate or delayed addition of STS. Similar studies found that doxorubicin, carmustine (BCNU), paclitaxel, or methotrexate did not reduce antitumor activity by STS. Because STS has the ability to remove free platinum-containing compounds, it has been extensively tested in the clinic as further described herein and is a highly effective ear protection compound for pediatric patients. Has been found to be.

One embodiment described herein is sodium thiosulfate. Another embodiment described herein is anhydrous sodium thiosulfate. In another embodiment, sodium thiosulfate is hydrate-free. In another embodiment, sodium thiosulfate does not contain sodium thiosulfate pentahydrate. In one embodiment, sodium thiosulfate comprises crystalline anhydrous sodium thiosulfate. In one embodiment, sodium thiosulfate comprises amorphous anhydrous sodium thiosulfate. In another embodiment, sodium thiosulfate comprises aqueous anhydrous sodium thiosulfate.

One embodiment is anhydrous sodium thiosulfate synthesized as described herein.

Another embodiment described herein is a method of synthesizing anhydrous sodium thiosulfate. In one embodiment, sodium thiosulfate is synthesized by reacting aqueous sodium sulfite with sulfur in the presence of a surfactant such as cetylpyridinium chloride (CPC). In one embodiment, about 1.0 molar equivalent of sodium sulfite is reacted with 1.1 molar equivalent of sulfur and 0.00013 molar equivalent of cetylpyridinium chloride. In one embodiment, the reaction is carried out at elevated temperatures. In another embodiment, the reaction is carried out at about 75 ° C to about 100 ° C for about 5 minutes to 5 hours. In another embodiment, the reaction is carried out at about 90 ° C. for about 5 minutes to 3 hours. In one aspect, the reactants are heated to about 90 ° C. The reaction is complete when the temperature reaches about 90 ° C. In another embodiment, the reactants are cooled after the reaction. In one aspect, the reactants are cooled to room temperature. In another embodiment, the reactants are cooled below 2 ° C. In another aspect, sodium thiosulfate is washed with a cleaning solvent. In another embodiment, sodium thiosulfate is washed with acetone. In another embodiment, the sodium thiosulfate is washed multiple times. In another embodiment, the sodium thiosulfate is washed once. In another embodiment, sodium thiosulfate is dehydrated by heating and / or filtration. In another embodiment the sodium thiosulfate is dehydrated using a dehydrating solvent. In one embodiment, the dehydrating solvent is alcohol. In another embodiment, the dehydrating solvent is methanol. In another embodiment, the dehydrating solvent is methanol heated to 30 ° C to 80 ° C. In another embodiment, sodium thiosulfate is dehydrated multiple times. In another embodiment, sodium thiosulfate is dehydrated once.

In one embodiment, anhydrous sodium thiosulfate is ground or micronized to a defined particle size. In one embodiment, anhydrous sodium thiosulfate comprises a particle size range of about 1 μm to about 500 μm, including all integers and fractions within the specified range. In one embodiment, the micronized anhydrous sodium thiosulfate particles have a particle size of about 1 μm to about 100 μm. In one embodiment, the micronized anhydrous sodium thiosulfate particles have a particle size of about 5 μm to about 50 μm. In another embodiment, the anhydrous sodium thiosulfate solid particles comprise a particle size distribution, including particles of any of the above particle sizes.

In another embodiment, the average particle size distribution (PSD) of anhydrous sodium thiosulfate particles is in the range of about 5 μm to about 300 μm, including all integers and fractions within the specified range. In one embodiment, the average particle size distribution of anhydrous sodium thiosulfate solid particles is about 5 μm, about 10 μm, about 15 μm, about 20 μm, 25 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm. , About 100 μm, about 120 μm, about 140 μm, about 160 μm, about 180 μm, about 190 μm, about 200 μm, about 220 μm, about 240 μm, about 260 μm, about 280 μm, or about 300 μm.

In one embodiment, the average particle size distribution d50 of anhydrous sodium thiosulfate solid particles is from about 5 μm to about 100 μm. In one embodiment, the average particle size distribution d50 of anhydrous sodium thiosulfate solid particles is from about 5 μm to about 50 μm. In one embodiment, the average particle size distribution d50 of anhydrous sodium thiosulfate solid particles is from about 10 μm to about 25 μm.

In another embodiment, the particle size distribution d90 of anhydrous sodium thiosulfate particles is about 100 μm or less. In one embodiment, the particle size distribution d90 of the anhydrous sodium thiosulfate solid particles is from about 50 μm or less to about 50 μm. In one embodiment, the particle size distribution d90 of the anhydrous sodium thiosulfate solid particles is about 25 μm or less (d90 ≦ 25 μm).

In another embodiment, the anhydrous sodium thiosulfate solid particles comprise a plurality of particle size distributions. In one embodiment, the anhydrous sodium thiosulfate solid particles may contain a plurality of independently combined average particle size distributions, each independent average particle size distribution including all integers and fractions within a specified range. , In the range of about 5 μm to about 100 μm. In another embodiment, the anhydrous sodium thiosulfate solid particles may contain a plurality of independently combined average particle size distributions, each independent average particle size distribution including all integers and fractions within a specified range. The range is about 5 μm to about 50 μm. In another embodiment, the anhydrous sodium thiosulfate solid particles comprise a combination of independently combined average particle size distributions. The average particle size distribution ranges from about 10 μm to about 30 μm, including all integers and fractions within the specified range. It is possible to combine any of the particle size distributions described above to provide the desired size distribution range.

The aforementioned size of anhydrous sodium thiosulfate particles can be calculated using standard techniques known to those of skill in the art. Illustrative techniques that can be used to measure the particle size of anhydrous sodium thiosulfate include laser diffraction analysis, light scattering (eg, dynamic light scattering), microparticle image analysis, elutriation, or aerosol mass analysis. Can be mentioned. The sample of anhydrous sodium thiosulfate particles can be measured as a dry sample or a wet sample. Any commercially available equipment for measuring particle size, such as Cilas, Brookhaven Instruments Corporation, Malvern Instruments, Horiba Scientific or Horiba Scientific. Wyatt) equipment can be used according to the manufacturer's instructions and according to the recommended operating procedures.

The particle size measured using the techniques described herein is a derived diameter with a normal distribution, or a mode with a mean, median (eg, median mass diameter), and mode of particle diameter size. It can be expressed as a distribution. The particle size distribution can be expressed as a number of diameter distribution, a surface area distribution, or a particle volume distribution. The average of the particle size distribution, the volume mean diameter (D [4,3] That _{d 43),} average surface area diameter (D [3,2] That _{d 32)} or average particle size (D [1,0] That _{d 10)} such Can be calculated and expressed in various ways. Since the value of the particle size distribution differs depending on the measurement method and the method of expressing the distribution, it is necessary to calculate the comparison of different average particle size distributions by the same method in order to make an accurate comparison. For example, a sample whose volume average diameter has been measured and calculated is measured under the same conditions using a sample whose volume average diameter has been measured and calculated, ideally the same measuring instrument. It is necessary to compare with the sample of. Therefore, the particular particle size distribution described herein is limited to any one type of method for measuring or calculating a particle size distribution (eg, diameter number distribution, surface area distribution, or particle volume distribution). Rather, the particle size values and their distributions for each method of measuring particle size described herein are shown.

Another embodiment described herein is anhydrous sodium thiosulfate produced by the methods described herein. Another embodiment is a means for preparing anhydrous sodium thiosulfate.

Another embodiment described herein is anhydrous sodium thiosulfate characterized by an X-ray powder diffraction (XRPD) pattern, collected from about 2 to about 40 ° 2θ using copper Kα radiation. In some cases, 10.52, 15.13, 17.71, 19.70, 21.09, 21.49, 21.84, 27.40, 28.96, 30.46, 31.81, 32.52. , 33.15, 37.40, or 38.16 ° 2 theta (2θ) ± 0.2, at least four peaks are included in this XRPD pattern, anhydrous sodium thiosulfate. In one embodiment, anhydrous sodium thiosulfate is characterized by an X-ray powder diffraction (XRPD) pattern when the XRPD is collected up to about 2 to about 40 ° 2θ using copper Kα radiation. , 10.52, 15.13, 19.70, 21.49, 21.84, 28.96, 30.46, 33.15, 37.40, or 38.16 ° 2 theta (2θ) ± 0. At least four peaks selected from 2 are included in this XRPD pattern. In one embodiment, anhydrous sodium thiosulfate is characterized by an XRPD pattern that is substantially similar to the XRPD pattern of FIG. 2A. In another embodiment, anhydrous sodium thiosulfate is characterized by an X-ray powder diffraction (XRPD) pattern, which includes at least one or at least two of the peaks shown in Table 5. , At least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10.

Another embodiment described herein includes cadmium of 0.1 μg / g or less, lead of 0.25 μg / g or less, arsenic of 0.75 μg / g or less, and mercury of 0.15 μg / g or less. Cobalt of 0.25 μg / g or less, vanadium of 0.5 μg / g or less, nickel of 1.0 μg / g or less, lithium of 12.5 μg / g or less, antimony of 4.5 μg / g or less, Anhydrous sodium thiosulfate comprising 15.0 μg / g or less of copper, 1500 ppm or less of methanol, 3% (w / w) or less of water, and 1.5% (w / w) of total impurities. Is.

Another embodiment described herein is anhydrous sodium thiosulfate, which is essentially free of sodium thiosulfate pentahydrate. In one embodiment, anhydrous sodium thiosulfate is less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.05%, or less than 0.001% sodium thiosulfate. Including Japanese products.

Another embodiment described herein is an assay for measuring the concentration of cisplatin. In one aspect, the assay comprises measuring cisplatin concentration using HPLC and UV detection and comparing retention time and peak area to a standard curve of cisplatin concentration assayed under similar conditions. Another embodiment described herein is a means for calculating the cisplatin concentration described herein.

Another embodiment described herein is an assay for determining the cisplatin binding capacity of a composition of sodium thiosulfate. The sodium thiosulfate composition can be a pharmaceutical composition of sodium thiosulfate pentahydrate, anhydrous sodium thiosulfate, aqueous anhydrous sodium thiosulfate, or sodium thiosulfate. The assay involves combining various concentrations of sodium thiosulfate with a concentration of cisplatin and then measuring the apparent decrease in cisplatin concentration over time using HPLC and UV detection. In one aspect, the molar ratio of sodium thiosulfate to cisplatin comprises 10: 1, 7: 1, 6: 1, 5: 1, 3: 1, 2: 1, or 1: 1. In one aspect, the molar ratio of sodium thiosulfate to cisplatin comprises 10: 1, 6: 1, or 5: 1. In one aspect, the apparent decrease in cisplatin concentration due to binding with sodium thiosulfate becomes linear over time. In another embodiment, the cisplatin concentration is measured after mixing with sodium thiosulfate ~ about 5 minutes and every 10 minutes, 20 minutes, 30 minutes, or 60 minutes for 0.5 hours, 1 hour, 2 hours, Measure for 3 hours, 4 hours, 5 hours, or 6 hours. In one aspect, the cisplatin concentration is measured ~ about 5 minutes after mixing with sodium thiosulfate and measured every 30 minutes for 2 hours. In one aspect, the mixed mode C-18 chromatography column used in the assay comprises both hydrophobic interaction and ion exchange function. In another embodiment, the HPLC run time of the assay is about 2 minutes, about 5 minutes, about 7.5 minutes, about 10 minutes, or about 15 minutes. In one aspect, the HPLC execution time is about 5 minutes or about 10 minutes. In another embodiment, cisplatin elutes from HPLC under assay conditions after about 1.5 to about 2.5 minutes. In one aspect, cisplatin elutes from HPLC under assay conditions after about 2 minutes. In another embodiment, sodium thiosulfate elutes from HPLC under assay conditions after about 5 to about 7.0 minutes. In one aspect, cisplatin elutes from HPLC under assay conditions after about 6 minutes.

Another embodiment described herein is a means for determining the ability of sodium thiosulfate to bind to cisplatin as described herein.

Without being bound by any theory, factors affecting cisplatin binding by sodium thiosulfate in the assays described herein include temperature, relative concentration of sodium thiosulfate, and mixing cisplatin with sodium thiosulfate. The elapsed time from that time to the HPLC measurement can be mentioned. The HPLC autosampler allows for tight temperature control, facilitating sample preparation and analysis. In addition, the changes in cisplatin concentration that occur in this method are not at a single point in time, but over time. Using this method, it is possible to calculate the kinetics under given conditions or half-life and make comparisons between different samples of sodium thiosulfate.

Another embodiment described herein is for measuring the binding capacity of sodium thiosulfate to cisplatin based on the apparent reduction in cisplatin concentration after combining various molar ratios of cisplatin and sodium thiosulfate. An assay, the method comprises mixing various molar ratios of sodium thiosulfate with a predetermined amount of cisplatin, incubating the mixture for a period of time, and analyzing the concentration of cisplatin. In one aspect, the molar ratio of sodium thiosulfate to cisplatin comprises 10: 1 to 1: 1. In one aspect, the molar ratio of sodium thiosulfate to cisplatin comprises 10: 1, 7: 1, 6: 1, 5: 1, 3: 1, 2: 1, or 1: 1. In one aspect, the mixture is incubated and analyzed at about 25 ° C. for about 5 minutes, about 35 minutes, about 65 minutes, about 95 minutes, and about 125 minutes. In another embodiment, the concentration is analyzed using HPLC with a mixed mode C-18 chromatography column with UV detection at a column temperature of 35 ° C., a flow rate of 400 μL / min, and 220 nm. In one embodiment, the HPLC method involves gradienting 100% buffer A (atonitrile aqueous solution of 0.5 mM ammonium formate at pH 4; water: acetonitrile 9: 1) in 3 minute increments, followed by 90% buffer A and A 10% buffer B (atonitrile aqueous solution of 200 mM ammonium formate at pH 4; water: acetonitrile 7: 3) is graded in 3.5 minute increments, and then 100% buffer A is graded in 4.5 minute increments. Including that.

Another embodiment described herein is a pharmaceutical composition or formulation comprising sodium thiosulfate. In one aspect, sodium thiosulfate comprises anhydrous sodium thiosulfate. The preparation is suitable for administration via any conventional route including intravenous, subcutaneous, intramuscular, intraperitoneal, intrathecal, oral, rectal, vaginal, or a combination thereof. In one embodiment, the product is administered intravenously.

In one embodiment, the pharmaceutical compositions described herein provide a composition of sodium thiosulfate for administration to a subject. Sodium thiosulfate can be administered, for example, to a subject, or a subject in need thereof.

Another embodiment described herein is a pharmaceutical composition comprising sodium thiosulfate. In one aspect, the composition comprises sodium thiosulfate and one or more pharmaceutically acceptable excipients. In another embodiment, the composition comprises sodium thiosulfate and a buffer. In another embodiment, the composition comprises anhydrous sodium thiosulfate and a buffer. In one aspect, the composition comprises a liquid formulation of anhydrous sodium thiosulfate and a buffer. In another embodiment, the composition is a dry or lyophilized composition comprising sodium thiosulfate and one or more buffers reconstituted with sterile water for injection prior to administration. In another embodiment, the composition comprises aqueous anhydrous sodium thiosulfate, one or more buffers, and a solvent. As used herein, the term "aqueous anhydrous sodium thiosulfate" refers to anhydrous sodium thiosulfate solubilized in an aqueous solvent. In another embodiment, the composition comprises aqueous anhydrous sodium thiosulfate, one or more buffers, one or more pH regulators, and a solvent. In another embodiment, the composition comprises aqueous anhydrous sodium thiosulfate, one or more buffers, one or more pH regulators, solvents, and one or more preservatives, saline, carriers, or pharmaceutically. Contains acceptable excipients. In one embodiment, the contents contained in the pharmaceutical preparation are as shown in Table 1.

In another embodiment, the pharmaceutical product comprises aqueous anhydrous sodium thiosulfate and water. In another embodiment, the pharmaceutical product comprises aqueous anhydrous sodium thiosulfate, water, a buffer, and one or more pH adjusters. In another embodiment, the pharmaceutical product comprises aqueous anhydrous sodium thiosulfate, water, a phosphate buffer, and one or more pH regulators that bring the pH to about 6.5. In another embodiment, the pharmaceutical product comprises aqueous anhydrous sodium thiosulfate, water, a borate buffer, and a pH of about 8.5-8.8. Contains one or more pH regulators. In another embodiment, the pharmaceutical product comprises aqueous anhydrous sodium thiosulfate, water, glycine, and a pH of about 8.5-8.9. Contains one or more pH regulators. In another embodiment, the pharmaceutical product comprises aqueous anhydrous sodium thiosulfate, water, tris (hydroxymethyl) aminomethane (tromethamine) buffer, and one or more pH regulators that bring the pH to about 8.5-8.9. include. In one embodiment, the pharmaceutical formulation comprises one of the formulations shown in Table 2. The following formulations are exemplary and the buffer identity and concentration can be adjusted in the range of about 0.001M to about 0.5M, adjusting mg / mL and weight percent accordingly. You may.

In one embodiment, the formulation is about 0.1M, about 0.2M, about 0.3M, about 0.4M, about 0.5M, about 0.6M, about 0.7M, about 0.8M, about. 0.9M, about 1.0M, about 1.1M, about 1.2M, about 1.3M, about 1.4M, about 1.5M, about 1.6M, about 1.7M, about 1.8M, about Contains 1.9 M, or about 2.0 M, aqueous anhydrous sodium thiosulfate.

In another embodiment, the formulation is about 0.1M to about 2.0M, about 0.1M to about 0.5M, about 0.1M to about 0.6M, about 0.1M to about 0.7M, About 0.1M to about 0.8M, about 0.1M to about 1.0M, about 0.2M to about 0.5M, about 0.2M to about 0.6M, about 0.2M to about 0.7M, About 0.2M to about 0.8M, about 0.2M to about 1.0M, about 0.3M to about 0.5M, about 0.3M to about 0.6M, about 0.3M to about 0.7M, About 0.3M to about 0.8M, about 0.3M to about 1.0M, about 0.4M to about 0.5M, about 0.4M to about 0.6M, about 0.4M to about 0.7M, About 0.4M to about 0.8M, about 0.4M to about 1.0M, about 0.5M to about 0.6M, about 0.5M to about 0.7M, about 0.5M to about 0.8M, Includes about 0.5M to about 1.0M, about 0.6M to about 0.7M, about 0.6M to about 0.8M, or about 0.6M to about 1.0M aqueous anhydrous sodium thiosulfate.

In another embodiment, the formulation comprises about 20 mg / mL, about 40 mg / mL, about 60 mg / mL, about 80 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, Includes about 180 mg / mL, about 200 mg / mL, about 220 mg / mL, about 240 mg / mL, about 260 mg / mL, about 280 mg / mL, about 300 mg / mL, or about 320 mg / mL aqueous anhydrous sodium thiosulfate.

In another embodiment, the formulation is about 10 mg / mL, about 320 mg / mL, about 10 mg / mL, about 80 mg / mL, about 10 mg / mL, about 100 mg / mL, about 10 mg / mL, about 110 mg / mL, About 10 mg / mL, about 120 mg / mL, about 10 mg / mL, about 160 mg / mL, about 20 mg / mL, about 80 mg / mL, about 20 mg / mL, about 100 mg / mL, about 20 mg / mL, about 110 mg / mL, About 20 mg / mL, about 120 mg / mL, about 20 mg / mL, about 160 mg / mL, about 30 mg / mL, about 80 mg / mL, about 30 mg / mL, about 100 mg / mL, about 30 mg / mL, about 110 mg / mL, About 30 mg / mL, about 120 mg / mL, about 30 mg / mL, about 160 mg / mL, about 40 mg / mL, about 80 mg / mL, about 40 mg / mL, about 100 mg / mL, about 40 mg / mL, about 110 mg / mL, About 40 mg / mL, about 120 mg / mL, about 40 mg / mL, about 160 mg / mL, about 60 mg / mL, about 80 mg / mL, about 60 mg / mL, about 100 mg / mL, about 60 mg / mL, about 110 mg / mL, About 60 mg / mL, about 120 mg / mL, about 60 mg / mL, about 160 mg / mL, about 80 mg / mL, about 100 mg / mL, about 80 mg / mL, about 110 mg / mL, about 80 mg / mL, about 120 mg / mL, Includes about 80 mg / mL, about 160 mg / mL, about 100 mg / mL, about 110 mg / mL, about 100 mg / mL, about 120 mg / mL, or about 100 mg / mL, about 160 mg / mL aqueous anhydrous sodium thiosulfate.

In another embodiment, the formulation comprises about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, about 14%, about 16%, about 18%, It contains about 20%, about 22%, about 24%, about 26%, about 28%, about 30%, or about 32% by weight of aqueous anhydrous sodium thiosulfate.

In another embodiment, the formulation comprises about 1% to about 32%, about 1% to about 8%, about 1% to about 10%, about 1% to about 11%, about 1% to about 12%, About 1% to about 16%, about 2% to about 8%, about 2% to about 10%, about 2% to about 11%, about 2% to about 12%, about 2% to about 16%, about 3 % ~ About 8%, about 3% ~ about 10%, about 3% ~ about 11%, about 3% ~ about 12%, about 3% ~ about 16%, about 4% ~ about 8%, about 4% ~ About 10%, about 4% to about 11%, about 4% to about 12%, about 4% to about 16%, about 6% to about 8%, about 6% to about 10%, about 6% to about 11 %, About 6% to about 12%, about 6% to about 16%, about 8% to about 10%, about 8% to about 11%, about 8% to about 12%, about 8% to about 16%, It contains about 10% to about 11%, about 10% to about 12%, or about 10% to about 16% by weight of aqueous anhydrous sodium thiosulfate.

In one embodiment described herein, the formulation comprises one or more buffers. A typical buffer is a pharmaceutically acceptable buffer. In one embodiment, the one or more buffers are acetic acid, acetylsalicylic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, bicarbonate, boric acid, butanoic acid, butyric acid, cerebral acid, cerebral sulfone. Acids, carbonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecyl sulfate, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerophosphate, glycine, glycricin, glucoheptanoic acid, gluconic acid, glutamic acid, glutaric acid, Glycolic acid, hemi-sulfate, heptanic acid, hexanoic acid, hyporic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, Mutic acid, naphthalenesulfonic acid, naphthylic acid, nicotinic acid, nitrite, oxalic acid, pelargone, phosphoric acid, propionic acid, pyruvate, saccharin, salicylic acid, sorbic acid, succinic acid, sulfuric acid, tartrate acid, thiocyanic acid, thioglycolic acid. , Thiosulfate, tosylic acid, undecylene acid, MES, bis-trismethane, ADA, ACES, bis-trispropane, PIPES, MOPSO, colamine chloride, MOPS, BES, TES, HEEPS, DIPSO, MOBS, acetamide glycine, TAPSO, TEA , POPSO, HEPPSO, EPS, HEPPS, Tricin, Tris (Hydroxymethyl) Aminomethane (Trometamin), Glycinamide, Glysing Lysine, HEPBS, Bicin, TAPS, AMPB, CHES, AMP, AMPSO, CAPSO, CAPS, CABS, Includes combinations or salts thereof. In one embodiment, the buffer is phosphate, sulfate, carbonate, formate, acetate, propionate, butaneate, lactate, glycine, maleate, pyruvate, citrate, aconite. Salt, isocitrate, α-ketoglutarate, succinate, fumarate, malate, oxaloacetate, asparagate, glutamate, tris (hydroxymethyl) aminomethane (tromethamine), combinations thereof, Or it contains one or more of those salts. In one embodiment, the buffer is phosphate, glycine, tris (hydroxymethyl) aminomethane (tromethamine), or borate. In one embodiment, the buffer is borate. In one embodiment, the buffer is phosphate. In one embodiment, the buffer is glycine. In one embodiment, the buffer is tris (hydroxymethyl) aminomethane (tromethamine).

In another embodiment, the concentration of one or more buffers is from about 0.001M to about 0.5M. In one embodiment, the concentration of one or more buffers is about 0.005M to about 0.2M, about 0.01M to about 0.1M, about 0.005M to about 0.05M, about 0.01M to about 0. It is 05M, or about 0.005M to about 0.01M. In one embodiment, the concentration of one or more buffers is about 0.005M, about 0.075M, about 0.01M, about 0.02M, about 0.05M, about 0.1M, about 0.2M, or about 0. It is .5M. In one aspect, the concentration of one or more buffers is about 0.01M. In another embodiment, the concentration of one or more buffers is about 0.05M.

In another embodiment, the pharmaceutical product comprises one or more buffers that are titrated with one or more pharmaceutically acceptable acids or bases for the purpose of pH adjustment. In one embodiment, the pharmaceutical product has a pH of about 2 to about 10, about 3 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 5 to about 6, and about 5 to about 7. , About 5 to about 8, about 6.0 to about 6.5, about 6 to about 7, about 6.5 to about 7, or about 6 to about 8. In one embodiment, the pharmaceutical product has a pH of about 5.0, about 5.5, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about. It is 6.6, about 6.7, about 6.8, about 6.9, about 7.0, or about 7.5. In one aspect, the pharmaceutical product has a pH of about 6.5.

In another embodiment, the pharmaceutical product comprises one or more buffers that are titrated with one or more pharmaceutically acceptable acids or bases for the purpose of adjusting the pH to about 6.5. Acids and bases are typically selected to match the ions present in the buffer and solution. In one embodiment, the pH is increased by adding a Group IA hydroxide. In one aspect, the hydroxide may be sodium hydroxide or potassium hydroxide. In another embodiment, the pH is lowered by adding an acid (ie, a proton donor). Any pharmaceutically acceptable acid can be used. In one embodiment, the acid is phosphoric acid. In another embodiment, the acid is hydrochloric acid. In one embodiment, both sodium hydroxide and hydrochloric acid (or phosphoric acid) are added to the formulation to titrate the pH to about 6.5.

One embodiment described herein is a pharmaceutical formulation as shown in Table 3.

Another embodiment described herein is a pharmaceutical formulation comprising about 0.25 M to about 1.0 M aqueous anhydrous sodium thiosulfate, a buffer of about 1.0 mM to about 500 mM and pH 5-9, and water. Is. In one aspect, the pharmaceutical formulation comprises about 40 mg / mL, about 160 mg / mL aqueous anhydrous sodium thiosulfate, about 1.4 mg / mL pH 5-8 phosphate buffer, and water. In another embodiment, the pharmaceutical formulation comprises from about 4% to about 16% aqueous anhydrous sodium thiosulfate, about 0.14% pH 5-8 sodium phosphate buffer, and water. In another embodiment, the pharmaceutical formulation comprises about 40 mg / mL, about 160 mg / mL aqueous anhydrous sodium thiosulfate, about 0.25 mg / mL borate buffer with a pH of 6-9, and water. In another embodiment, the pharmaceutical formulation comprises from about 4% to about 16% aqueous anhydrous sodium thiosulfate, about 0.023% pH 6-9 borate buffer, and water. In another embodiment, the pharmaceutical formulation comprises about 40 mg / mL, about 160 mg / mL aqueous anhydrous sodium thiosulfate, about 0.75 mg / mL glycine buffer with a pH of 6-9, and water. In another embodiment, the pharmaceutical formulation comprises from about 4% to about 16% aqueous anhydrous sodium thiosulfate, about 0.069% pH 6-9 glycine buffer, and water. In another embodiment, the pharmaceutical preparation is composed of about 40 mg / mL, about 160 mg / mL aqueous anhydrous sodium thiosulfate, and about 1.21 mg / mL of tris (hydroxymethyl) aminomethane (tromethamine) buffer having a pH of 6-9. Including with water. In another embodiment, the pharmaceutical preparation comprises about 4% to about 16% aqueous anhydrous sodium thiosulfate, about 0.11% pH 6-9 pH 6-9 tris (hydroxymethyl) aminomethane (tromethamine) buffer, and water. include.

Another embodiment described herein is a pharmaceutical formulation comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M and pH 6.5 sodium phosphate, and water. In one aspect, the pharmaceutical formulation comprises about 80 mg / mL aqueous anhydrous sodium thiosulfate, about 1.4 mg / mL and pH 6.5 sodium phosphate, and water. In another embodiment, the pharmaceutical formulation comprises about 8% aqueous anhydrous sodium thiosulfate and about 0.14% and pH 6.5 sodium phosphate.

Another embodiment described herein is a pharmaceutical formulation comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M and pH 8.6-8.8 boric acid, and water. In one aspect, the pharmaceutical formulation comprises about 80 mg / mL aqueous anhydrous sodium thiosulfate, about 0.25 mg / mL boric acid with a pH of 8.6 to 8.8, and water. In another embodiment, the pharmaceutical formulation comprises about 8% aqueous anhydrous sodium thiosulfate and about 0.023% pH 8.6-8.8 boric acid.

Another embodiment described herein is a pharmaceutical product comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M and pH 8.5-8.9 glycine, and water. It is a preparation. In one aspect, the pharmaceutical formulation comprises about 80 mg / mL aqueous anhydrous sodium thiosulfate, about 0.75 mg / mL, about 3.8 mg / mL and pH 8.5-8.9 glycine, and water. In another embodiment, the pharmaceutical formulation comprises about 8% aqueous anhydrous sodium thiosulfate and about 0.069% to about 0.35% and pH 8.5-8.9 glycine.

Another embodiment described herein is about 0.5 M aqueous anhydrous sodium thiosulfate and tris (hydroxymethyl) aminomethane at about 0.01 M to about 0.05 M and pH 8.5-8.9. It is a pharmaceutical preparation containing tromethamine) and water. In one aspect, the pharmaceutical formulations are such as about 80 mg / mL aqueous anhydrous sodium thiosulfate and about 1.2 mg / mL, about 3.6 mg / mL pH 8.5-8.9 tris (hydroxymethyl) aminomethane. It contains tromethamine) and water. In another embodiment, the pharmaceutical product comprises about 8% aqueous anhydrous sodium thiosulfate and about 0.1% to about 0.33% pH 8.5-8.9 tris (hydroxymethyl) aminomethane (tromethamine). And water.

Another embodiment described herein is a pharmaceutical composition comprising an aqueous sodium thiosulfate solution and one or more pharmaceutically acceptable excipients.

Another embodiment described herein is a pharmaceutical composition comprising an aqueous sodium thiosulfate solution and one or more pharmaceutically acceptable buffers. In one embodiment, the pharmaceutical composition has a pH of 4-8. In another embodiment, the pharmaceutical composition is pH 5-7. In another embodiment, the pharmaceutical composition has a pH of 6-7. In another embodiment, the pharmaceutical composition has a pH of 6-8. In another embodiment, the pharmaceutical composition has a pH of about 6. In another embodiment, the pharmaceutical composition has a pH of about 6.5. In another embodiment, the pharmaceutical composition has a pH of about 7. In another embodiment, the pharmaceutical composition has a pH of about 7.5.

Another embodiment described herein is a pharmaceutical composition comprising an aqueous sodium thiosulfate solution, one or more pharmaceutically acceptable buffers, and one or more salts. In one embodiment, in one embodiment, the one or more salts are sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium sulfate, potassium sulfate, magnesium sulfate, calcium sulfate, ammonium chloride, ammonium carbonate, ammonium phosphate, ammonium sulfate. , Potassium citrate, potassium phosphate, among others, potassium lactate, sodium acetate, sodium citrate, sodium lactate, sodium phosphate. In one embodiment, the concentration of one or more salts is from about 0.001M to about 0.5M. In another embodiment, the concentration of one or more salts is about 0.001M, about 0.005M, about 0.01M, about 0.05M, about 0.1M, about 0.2M, or about 0.5M. be. In one embodiment, the concentration of one or more salts is from about 0.05M to about 0.2M.

Another embodiment described herein is from about 0.2 M to about 2 M aqueous sodium thiosulfate solution, from about 0.001 M to about 0.05 M pharmaceutically acceptable buffer, and from about 0.005 M. A pharmaceutical composition comprising about 0.05 M of a pharmaceutically acceptable salt. In one aspect, the pharmaceutical composition has a pH of about 6-8. In one embodiment, the pharmaceutical composition comprises about 1 M sodium thiosulfate, about 0.05 M pharmaceutically acceptable buffer, and about 0.05 M and about 6-8 pH pharmaceutically acceptable salts. It is a pharmaceutical composition containing.

Another embodiment described herein is a sodium thiosulfate pharmaceutical composition that is essentially free of borate ions. In one embodiment, the sodium thiosulfate composition comprises less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.05%, or less than 0.001% borate ions. including. In one aspect, the sodium thiosulfate composition comprises phosphate ions instead of borate ions.

Another embodiment is a method of producing a pharmaceutical sodium thiosulfate preparation. In one embodiment, such compositions are prepared by: (i) combining sodium thiosulfate with a solvent, and optionally one or more pharmaceutically acceptable excipients, and (ii) a liquid. Alternatively, it is produced by transferring a single or multiple doses of the suspension to a suitable container and (iii) sealing the container. In one embodiment, the liquid or suspension is filtered and / or sterilized before or after transfer to a suitable container. In one aspect, the container is an injectable vial or syringe.

One embodiment is a method for preparing an anhydrous sodium thiosulfate-containing preparation, which comprises combining anhydrous sodium sulfate with one or more buffers and solvents. The method further comprises adjusting the pH with a pharmaceutically acceptable acid or base. In one embodiment, the buffer is sodium phosphate and the acids and bases are hydrochloric acid and sodium hydroxide. The method further comprises filtering the solution, transferring the solution to a suitable receptacle, sealing the receptacle and sterilizing the formulation. In one aspect, the pharmaceutical product is sterilized by filtration and autoclaving.

Another embodiment is a preparation containing anhydrous sodium thiosulfate produced by the method described herein. Another embodiment is a means for preparing a pharmaceutical product containing anhydrous sodium thiosulfate.
Another embodiment described herein is the pharmaceutical composition of the STS formulation described herein. One or more excipients that can be included in the pharmaceutical composition are as follows:
(I) Buffering agent: Sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, pyruvate, etc. to keep the pH within the desired range. Physiologically acceptable buffer. Alternatively, an antacid such as Mg (OH) ₂ or ZnCO _{3 may be used.} The buffer capacity can be adjusted to match the conditions most sensitive to pH stability.
(Ii) Isotonic modifier: A medium that minimizes labor pain that is thought to be caused by cell damage caused by the difference in osmotic pressure at the injection depot. Examples are glycerin and sodium chloride. The effective concentration can be calculated by osmotic pressure measurement in which the osmolality of serum is assumed to be 285-315 mOsmol / kg.
(Iii) Preservatives and / or antibacterial agents: For parenteral preparations of multiple doses, it may be necessary to add a sufficient concentration of preservatives to minimize the risk of infection to the subject at the time of injection. Those with established regulatory requirements. Typical preservatives include m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosol, sorbic acid, potassium sorbate, benzoic acid, Examples include chlorocresol and benzalconium chloride.
(Iv) Stabilizer: An agent that achieves stabilization by enhancing protein stabilizing power, destabilizing a denatured state, or by directly binding an excipient to a protein. Stabilizers include amino acids such as alanine, arginine, aspartic acid, glycine, histidine, lysine and proline, sugars such as glucose, sucrose and trehalose, polyols such as glycerol, mannitol and sorbitol, salts such as potassium phosphate and sodium sulfate. It can be a chelating agent such as EDTA, hexaphosphate, a ligand such as a divalent metal ion (zinc, calcium, etc.), other salts, or an organic molecule such as a phenol derivative. In addition, oligomers or polymers such as cyclodextrin, dextran, dendrimer, polyethylene glycol, polyvinylpyrrolidone, protamine or human serum albumin may be used.
(V) Anti-adsorption agent: A container of composition (eg, poloxamer (Pluronic F-68), using predominantly ionic or ion-ionic surfactants or other proteins or soluble polymers. ), PEG dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA and gelatin) competitively coated or adsorbed on the inner surface. The concentration selected and the type of excipient will vary depending on the effects to be avoided, but usually a monolayer of surfactant is formed at the interface just above the CMC value.
(Vi) Freeze-drying or antifreeze: During lyophilization or spray-drying, the destabilizing effects due to hydrogen bond cleavage and moisture removal can be offset by excipients. Sugars and polyols may be used for this purpose, but the corresponding positive effects have also been observed with respect to surfactants, amino acids, non-aqueous solvents, and other peptides. Trehalose is particularly effective in reducing water aggregation and also improves the thermal stability that can be caused by exposing the hydrophobic groups of proteins to water. It is also known that mannitol and sucrose can be used alone or in combination with each other, and increasing the proportion of mannitol or sucrose enhances the physical stability of the lyophilized cake. .. In addition, mannitol may be combined with trehalose. Trehalose may also be combined with sorbitol or sorbitol may be used as the sole protective agent. Starch or starch derivatives may also be used.
(Vii) Antioxidants: Antioxidants such as ascorbic acid, ectin, methionine, glutathione, monothioglycerol, morin, polyethyleneimine (PEI), propyl gallate, vitamin E, citric acid, EDTA, hexaphosphate, thio Chelating agents such as glycolic acid.
(Viii) Thickener or Viscosity Enhancer: Delays sedimentation of particles in vials and syringes, facilitates particle mixing and resuspension, and facilitates suspension infusion (ie, syringe plan). Used for the purpose of (attenuating the force applied to the jar). Suitable thickeners or viscosity enhancers are, for example, polymer thickeners such as Carbopol 940, Carbopol Ultraz 10, hydroxypropylmethyl cellulose (hypromerose, HPMC) or diethylaminoethyl cellulose (DEAE or DEAE-C), colloidal magnesium silicate. Cellulose derivatives such as (Vegum) or sodium silicate, hydroxyapatite gels, tricalcium phosphate gels, xanthans, caragenans such as Satiagum UTC 30, aliphatic polys (hydroxyic acids) such as poly (d, l- or l-). Lactic acid) (PLA) and poly (glycolic acid) (PGA), and their copolymers (PLGA), d, l-lactide terpolymers, glycolides and caprolactones, poroxamers, hydrophilic poly (oxyethylene) blocks and hydrophobic Sexual poly (oxypropylene) blocks, thereby poly (oxyethylene) -poly (oxypropylene) -poly (oxyethylene) triblocks (eg, Pluronic ™), polyethylene glycol terephthalate / polybutylene terephthalate copolymers. , Polyether ester copolymers such as sucrose isobutylate butyrate (SAIB), dextran or derivatives thereof, combinations of dextran and PEG, polydimethylsiloxane, collagen, chitosan, polyvinyl alcohol (PVA) and derivatives, polyalkylimide, poly ( Acrylamide-codieallyldimethylammonium (DADMA)), polyvinylpyrrolidone (PVP), glycosaminoglycan (GAG), such as dermatane sulfate, chondroitin sulfate, keratane sulfate, heparin, heparan sulfate, hyaluronic acid, ABA triblock or hydrophobic It constitutes an AB block copolymer composed of a sex A block, such as polylactide (PLA) or poly (lactide-co-glycolide) (PLGA), and a hydrophilic B block, such as polyethylene glycol (PEG) or polyvinylpyrrolidone. If such block copolymers and the poloxamers described above have reverse heat gelling behavior (fluid state at room temperature that facilitates administration, and gel state above the sol-gel transition temperature at body temperature after injection). There is.
(IX) Diffusing agent: Permeability of connective tissue through hydrolysis of extracellular matrix components in the interstitial cavity, such as, but not limited to, hyaluronic acid, which is a polysaccharide found in the intercellular space of connective tissue. change. Diffusing agents, such as, but not limited to, hyaluronidase, temporarily reduce the viscosity of the extracellular matrix and promote the diffusion of the injected drug.
(X) Other auxiliary agents: wetting agents, viscosity modifiers, antibiotics, hyaluronidase, etc. Acids or bases such as hydrochloric acid or sodium hydroxide are required and auxiliary agents for pH adjustment during production.

The aforementioned list does not mean that it is exclusive, but instead a class of excipients and specific excipients that may be used in the pharmaceutical as described herein. It is merely representative.

The STS formulation may be provided as a liquid, suspension, or dry composition.

In one embodiment, the STS formulation is a sterile liquid composition. This product may be administered intravenously using direct venipuncture or an intravenous line.

In one embodiment, the pharmaceutical composition is a sterile solution.

In another embodiment, the STS formulation is a dry composition. Suitable drying methods are, for example, spray drying and lyophilization (lyophilization). In one aspect, the STS product is prepared as a solution and dried by lyophilization. In another embodiment, the STS preparation is prepared as a reconstituted dry composition just prior to use in sterile water for injection, which is then administered intravenously either directly by venipuncture or by an intravenous line.

In another embodiment, the composition is reconstituted with sterile water for injection, PBS, saline or other sterile parenteral compatible solution to produce a solution suitable for injection. It is a possible dry or freeze-dry composition. In one aspect, the composition comprises from about 20 mg to 32 g anhydrous sodium thiosulfate. In one aspect, the composition comprises about 98% by weight anhydrous sodium thiosulfate. In one aspect, the composition comprises one or more buffers of about 1% to 2% by weight. When the specified amount of sterile water for injection was added, the reconstituted dried or lyophilized composition was about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M and pH 6.5. Includes sodium phosphate and water.

Pharmaceutical compositions suitable for administration by injection include sterile aqueous solutions, suspensions or dispersions, and sterile powders or lyophilized products for the immediate preparation of sterile injectable solutions or dispersions.

Suitable solvents for intravenous administration include sterile water for injection, phosphate buffered saline (PBS), saline, or Ringer's solution. In all cases, the composition should be sterile and fluid to the extent that easy injectability exists. Preferred for pharmaceutical formulations are those that are stable under manufacturing and storage conditions and require protection against the contaminating effects of microorganisms such as bacteria and fungi. In general, the relevant solvent or carrier is as a solvent or dispersion medium containing, for example, water, buffers, ethanol, polyols (eg, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. There is no problem. Prevention of microbial action can be achieved with various antibacterial and antifungal agents such as parabens, chlorobutanol, phenols, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, such as sugars, polyhydric alcohols such as mannitol, amino acids, sorbitol, sodium chloride, or combinations thereof in the composition.

Certain injectable compositions are isotonic aqueous solutions or suspensions. Suppositories are preferably prepared from fatty emulsions or suspensions. The above compositions may be sterilized and / or adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution accelerators, salts for adjusting osmotic pressure, and / or It may also contain a buffer. In addition, it may also contain other therapeutically valuable substances. Each of the above compositions may be prepared according to conventional mixing, granulation, or coating methods and may contain from about 0.1 to 75%, or about 1 to 50%, active ingredients. In one embodiment described herein, the composition comprises about 7.5% aqueous anhydrous sodium thiosulfate, which is an active ingredient. When the present composition is a dry composition suitable for reconstruction, the content of sodium thiosulfate may be up to 98%.

A sterile injectable solution or suspension incorporates the required amount of sodium thiosulfate in a suitable solvent containing one or a combination of raw materials as needed, followed by filtration and / or sterilization. It may be done. Solutions or suspensions are typically prepared by incorporating the active compound into sterile water or sterile vehicles such as PBS and any excipients. In one aspect, sterilization is performed by autoclaving the final product in an injection vial. In the case of preparing a sterile injection solution with a sterile powder, vacuum drying and freeze drying are preferable as the preparation method. These dryings provide powders of active material and additional excipients from the previously sterile filtered solution.

Transmucosal or transdermal administration means are also possible. Suitable compositions for transdermal application contain an effective amount of a biologically active agent with a suitable carrier. Suitable carriers for transdermal delivery include absorbable, pharmacologically acceptable solvents that aid in passing through the host's skin. For example, a transdermal device is a backing member, a reservoir containing a compound optionally having a carrier, optionally a speed control barrier for delivering a compound of the host's skin at a controlled and predetermined rate over a long period of time. It has the shape of a bandage, including, which means that the device is secured to the skin.

For example, compositions suitable for topical application to the skin, eyes, or joints include, for example, aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, or the like, for delivery via aerosols. Something similar. Such a topical delivery system is particularly suitable for application to the skin. Therefore, it is particularly suitable for use in topical preparations such as cosmetics well known in the art. Such may contain solubilizers, stabilizers, tonicity enhancers, buffers, or preservatives.

As used herein, topical application may also involve inhalation or intranasal application. From a dry powder inhaler or aerosol spray presentation, with or without the use of a suitable propellant, from a pressurized container, pump, spray, nebulizer or nebulizer, in the form of a dry powder (alone, eg, with lactose). It is convenient to be able to deliver as a mixture, or as a mixture with mixed component particles, eg, a mixture with a phospholipid.

Pharmaceutical compositions and dosage forms that include one or more agents that reduce the rate of degradation of the compositions described herein as active ingredients are also described herein. Such agents, which are referred to herein as "stabilizers", include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, salts and sugars.

Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate. In one aspect, the composition comprises either of the formulations shown in the tables or examples described herein. Any ingredient in the formulations described herein is shown in the table or in the Examples. By enhancing, reducing, combining, substituting, or omitting those components, it is possible to provide a formulation containing about 100% by weight. Such compositions are disclosed herein as if they were expressly disclosed herein.

The effective amount of the therapeutically administered pharmaceutical active ingredient depends, for example, on the context and purpose of the treatment. As is recognized by those skilled in the art, the appropriate dose level for treatment is somewhat the concentration of the STS formulation, the administration regimen in which the STS formulation is used, the route of administration, and the size of the subject (body weight or body). It depends on the surface area) and the condition of the patient (age and general health). Therefore, the clinician can titrate the dose and change the route of administration to obtain the optimum therapeutic effect.

The frequency of dosing depends on the pharmacokinetic parameters of the therapeutic agent incorporated in the STS formulation being used. The composition is administered as a single dose, as two or more doses (which may or may not contain the same amount of the desired molecule), or a transplant device or It may be administered as a continuous infusion via a catheter. Further fine-tuning of the appropriate dosage is routinely performed by those skilled in the art and is within the range of tasks routinely performed by those skilled in the art. Appropriate dose response data can be used to confirm the appropriate dose.

Sodium thiosulfate may be administered, for example, once, twice, three times, four times, five times, six times, or more times a day. One or more doses may be administered, for example, over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or even more. One or more doses may be administered, for example, over a week, two weeks, three weeks, four weeks, or even more. One or more doses are, for example, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 It may be administered for months, 12 months, 1 year, 2 years, 3 years, 4 years, 5 years, more than 5 years, 10 years, decades, or even longer. One or more doses may be given regularly until the subject or the subject in need of it no longer requires treatment, prevention, or remission of ototoxicity.

In one embodiment, the pharmaceutical compositions described herein are administered simultaneously in single or multiple doses. For example, two or more identical doses are administered at one time. In another embodiment, two or more different doses are administered at one time. Such double or separate co-administration may be used to provide an effective amount of a pharmaceutical composition to a subject in need thereof.

In another embodiment, the pharmaceutical compositions described herein are used to enable treatment, prevention, delayed progression, delayed onset, remission, sign relief, or prevention of ototoxicity.

In one embodiment, the STS preparation is a composition in an amount sufficient to provide a therapeutically effective amount of sodium thiosulfate in a single application. In one embodiment, the STS preparation is applied for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, 1 month, 2 months. Only one application is sufficient over 3, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, or even longer.

The phrases and terms "injectable," "injectable," or "injectable" are used herein as they are dissolved in a liquid at a particular concentration (w / v) and a particular temperature. A specific force applied to the plunger of the syringe containing the STS formulation described in the document, a needle of a given inner diameter connected to the outlet of such a syringe, and a constant amount through the needle from the syringe. Refers to a combination of factors, such as the time required to extrude an STS formulation.

In one embodiment, the STS formulation is provided as a single dose. That is, the container to which the STS preparation is supplied contains one pharmaceutical dose.

In another embodiment, the composition is provided as a multi-dose composition. That is, it contains multiple therapeutic doses. It is preferred that the multi-dose composition comprises at least two doses. Such a multi-dose STS formulation may be used in different subjects who require it, or is intended for use in one subject, with the remaining doses after application of the initial dose. , Saved until needed.

In another embodiment, the STS formulation is configured in one or more containers. When targeting liquid or suspension compositions, it is preferred that the container be a single chamber syringe. When the dry composition is targeted, it is preferable that the container is a double chamber syringe. The first chamber of the dual chamber syringe is provided with the drying composition and the second chamber of the dual chamber syringe is provided with the reconstitution solution.

The dried composition is reconstituted before administering the dried STS formulation to the subject in need thereof. A container that can be reconstituted is a container provided with a dry STS formulation, such as a vial, syringe, dual chamber syringe, ampoule, or cartridge. The reconstitution is carried out by adding a predefined amount of the reconstitution solution to the dry composition. The reconstituted solution is a sterile liquid such as water for injection, phosphate buffered saline, isotonic saline, or other buffer, and additional preservatives and / or antibacterial agents such as benzyl alcohol and cresol. May contain excipients. The reconstituted solution is preferably sterile water for injection. Alternatively, the reconstituted solution is sterile phosphate buffered saline (PBS) or saline.

Another embodiment is a method of preparing a reconstituted composition comprising a therapeutically effective amount of an STS preparation and optionally one or more pharmaceutically acceptable excipients, wherein the method comprises a composition. Includes the step of contacting with a certain amount of reconstituted vehicle. The reconstituted STS preparation may then be administered via injection or other route.

Another embodiment is a reconstituted composition comprising a therapeutically effective amount of the STS formulation, a reconstituted vehicle, and optionally one or more pharmaceutically acceptable excipients.

Another embodiment is a prefilled syringe comprising a therapeutically effective amount of STS formulation and a solution or suspension optionally containing one or more pharmaceutically acceptable excipients. In one aspect, the syringe is filled with about 0.01 mL to about 5 mL of STS formulation, as described herein. In one embodiment, the syringe is about 0.05 mL to about 5 mL, about 1 mL to about 2 mL, about 0.1 mL to about 0.15 mL, about 0.1 mL, about 0.5 mL, about 0.15 mL to about 0.175 mL. , Or about 0.5 to about 5 mL. In one embodiment, the syringe is filled with 0.165 mL of the STS formulation described herein. In some embodiments, the syringe is about 0.01 mL, about 0.02 mL, about 0.03 mL, about 0.04 mL, about 0.05 mL, about 0.06 mL, about 0.07 mL, about 0.08 mL, about. 0.09 mL, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about It is filled with 1 mL, about 1.2 mL, about 1.5 mL, about 1.75 mL, about 2 mL, about 2.5 mL, about 3 mL, about 4 mL, or about 5 mL of the STS formulations described herein. Syringes are often filled in amounts above the desired dose suitable for administration to the patient, taking into account the waste due to "dead space" within the syringe and needle. Also, when the physician primes the syringe, a predetermined amount of waste may be present to prepare the patient for injection.

In one embodiment, the syringe is about 0.01 mL to about 5 mL (eg, about 0.01 mL to about 0.) Depending on the dosage route (eg, the amount of drug intended to achieve patent acquisition). 1 mL, about 0.1 mL to about 0.5 mL, about 0.2 mL to about 2 mL, about 0.5 mL to about 5 mL, or about 1 mL to about 5 mL) are filled with the STS formulation described herein. ..

In one embodiment, when the composition is intended for injection, the syringe will have a dosage of about 0.01 mL to about 5.0 mL of STS pharmaceutical solution or drug concentration of 0.1 mg, as described herein. It is filled with a suspension of / mL-40 mg / mL. In some embodiments, the syringe is about 0.01 mL, about 0.02 mL, about 0.03 mL, about 0.04 mL, about 0.05 mL, about 0.06 mL, about 0.07 mL, about 0.08 mL, about. 0.09 mL, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about It is filled with 1 mL, about 1.2 mL, about 1.5 mL, about 1.75 mL, about 2 mL, about 2.5 mL, about 3 mL, about 4 mL, or about 5 mL of the STS formulation described herein. It is possible to deliver to patients in need.

The outlet of the syringe containing the drug is reversibly sealed, allowing the sterility of the drug to be maintained. This sealing can be achieved by a sealing device known in the art such as luer locks or tamper-proof seals.

Another embodiment is a kit comprising one or more vials or prefilled syringes containing a solution or suspension of one or more STS formulations described herein. In one embodiment, such a kit comprises a vial or prefillable syringe containing the STS formulation as described herein in a blister pack or sealed sleeve. Blister packs or sleeves may be sterilized on the inside. In one aspect, the vials or prefillable syringes described herein may be placed inside such a blister pack or sleeve before being subjected to sterilization, eg, final sterilization. The kit may also include documentation containing prescribing information or instructions for use.

Such a kit may further include one or more needles for administration of the STS formulation as described herein. Such kits may further include instructions for use, drug labels, contraindications, warnings, or other relevant information. One embodiment described herein is a blister pack, syringe, one or more vials or prefilled syringes containing one or more STS formulations described herein, optionally. Specifically, it is a carton or package containing documents or instructions regarding administration, drug labels, contraindications, warnings, or other relevant information.

Vials or syringes may be sterilized using the final sterilization process. Such processes are sometimes used autoclave known processes, such as ethylene oxide or hydrogen peroxide (H 2 _{O 2)} sterilization process. The needles used in the syringe may be sterilized in the same manner as the kits described herein. In one aspect, the package is exposed to an autoclave or sterile gas until the outside of the package is sterilized. Following such a process, the outer surface of the syringe can be kept sterile for up to 6 months, 9 months, 12 months, 15 months, 18 months (while in the blister pack). It is considered to be 24 months or more. Therefore, in one embodiment, the shelf life of the prefilled syringes (in blister packs) described herein is up to 6 months, 9 months, 12 months, 15 months, 18 months. It can be months, 24 months, or more. In one embodiment, less than 1 in 1 million syringes have microorganisms detected on the outside of the syringe after 18 months of storage. In one aspect, the prefilled syringe is ^{sterilized using at least 10-6} guaranteed sterilization levels of ethylene oxide. In another embodiment, the prefilled syringe is ^{sterilized using at least 10-6} guaranteed sterilization levels of hydrogen peroxide. It is necessary to prevent significant amounts of sterile gas from entering the variable volume chamber of the syringe. As used herein, the term "significant amount" refers to the amount of gas that can cause an unacceptable change in the STS pharmaceutical solution or suspension in a variable volume chamber. In one embodiment, the sterilization process results in an alkylation of the STS formulation of 10% or less (preferably 5% or less, 2% or less, 1% or less, 0.5% or less, 0.1% or less). In one embodiment, the prefilled syringe is sterilized using ethylene oxide, but there is an ethylene oxide residue of 1 ppm or less, preferably 0.2 ppm or less on the outer surface of the syringe. In one embodiment, the prefilled syringe is sterilized with hydrogen peroxide, but there is a hydrogen peroxide residue of 1 ppm or less, preferably 0.2 ppm or less on the outer surface of the syringe. In another embodiment, the prefilled syringe is sterilized using ethylene oxide and the total amount of ethylene oxide residue found on the outside of the syringe and inside the blister pack is less than 0.1 mg. In another embodiment, the prefilled syringe is sterilized with hydrogen peroxide and the total amount of hydrogen peroxide residue found on the outside of the syringe and inside the blister pack is less than 0.1 mg. ..

Another embodiment described herein is a kit comprising sodium thiosulfate for administration to a subject. The kit includes a syringe, a needle, and a container for the STS formulation for use in the syringe when the composition of the liquid and suspension is targeted and the administration device is a simple subcutaneous syringe. It may be made to do. When the dry composition is targeted, one chamber containing the dry STS composition and a second chamber containing the reconstitution solution may be contained in the present container. In one embodiment, the injection device is such that the container containing the STS formulation engages the injection device and the liquid, suspension, or reconstituted dry composition in the container is directed to the outlet of the injection device. A subcutaneous syringe adapted for fluid connection. Examples of administration devices include, but are not limited to, subcutaneous syringes and pen syringes.

Another embodiment comprises a kit comprising a needle and a container containing the STS formulation composition, optionally further comprising a reconstitution solution, the container being adapted to be shared with the needle. In one aspect, the container is a prefillable syringe. In another embodiment, the container is a dual chamber syringe. In another embodiment, the STS formulation is provided as a lyophilized product in a sealed vial and the reconstitution solution is provided in another receptacle such as a sealed vial or a prefilled syringe. Resuspend the lyophilized product using the appropriate amount of reconstitution solution. In another aspect, the kit is provided with instructions, labels, or other printed matter.

Another embodiment is a cartridge containing the compositions described herein for use with a pen injector device. The cartridge may be provided with a single-dose or multiple-dose STS preparation.

In another embodiment, one or more STS formulations are administered simultaneously, with each STS formulation having distinct or associated biological activity.

In an alternative embodiment, the STS formulation is combined with a second biologically active compound in such a manner that it is first administered to a subject in need thereof and then a second compound. Is done. Alternatively, the STS pharmaceutical composition is administered to a subject in need of another compound after it has been administered to the same subject.

Another embodiment described herein is a method for reducing ototoxicity in a patient suffering from cancer and receiving platinum-based chemotherapy for the purpose of treating cancer (eg, a pediatric patient). The method comprises administering to the patient an effective amount of STS. In one aspect, the STS comprises one or more of the STS formulations described herein. STS has been found to significantly reduce the risk of ototoxicity, especially in the pediatric patient population. Therefore, one embodiment described herein is a method of reducing ototoxicity in a pediatric patient suffering from cancer and receiving platinum-based chemotherapy, the method providing an effective amount of STS to the pediatric patient. Including administration. In some embodiments, the pediatric patient is already ototoxic and administration of STS reduces the amount of future ototoxicity that the pediatric patient will suffer.

The risk of pediatric patients having detectable ototoxicity, such as deafness measured on a block scale of one or more, is significantly reduced by treatment with STS after administration of a cisplatin-based chemotherapeutic agent. The risk of ototoxicity is associated with pediatric patients not receiving STS. Therefore, in some embodiments, the probability that a pediatric patient will suffer from ototoxicity is about 10% to about 100%, about 30% to about 90, including each integer within the specified range, due to STS administration. % Or about 40% to about 70% reduction. In some embodiments, the risk of ototoxicity for pediatric patients is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80 due to STS administration. %, About 90%, or even about 100% reduction. In some embodiments, according to the hearing loss criteria defined by SHA, pediatric patients are at about 50% risk of ototoxicity.

Similarly, treatment of pediatric patients with STS has made it possible to further reduce long-term ototoxicity in pediatric patients suffering from cancer and receiving platinum-based chemotherapy. Pediatric patients after treatment with STS may develop ototoxicity weeks, months, or even years after continuous treatment with platinum-based chemotherapeutic agents. It has been known. Therefore, another embodiment described herein is a method of reducing long-term ototoxicity in a pediatric patient suffering from cancer and receiving platinum-based chemotherapy, the method of which is an effective amount of thiosulfate. Includes administration of sodium to pediatric patients.

As mentioned above, platinum-based chemotherapeutic agents such as cisplatin are believed to exert an ototoxic effect by concentrating on the ear cavity of a patient (eg, a pediatric patient). As further conceived herein, STS reduces the amount of platinum-based chemotherapeutic agent in the ear cavity by binding to the drug and reducing the drug accumulation in the ear cavity. It is possible. Another embodiment described herein is a method of reducing the concentration of cisplatin in the ear cavity of a pediatric patient suffering from cancer and receiving platinum-based chemotherapy, the method of which is an effective amount of thio. Includes administration of sodium sulfate to pediatric patients. In some embodiments, cisplatin levels in the ear cavity are about 50%, about 60%, about 70%, as compared to pediatric patients receiving platinum-based chemotherapy but not receiving STS. About 80%, about 90%, or about 100% lower. In some embodiments, the cisplatin concentration in the ear cavity is undetectable. In some embodiments, patients receiving STS are less susceptible to ototoxicity due to the reduced amount of platinum-based chemotherapeutic agent in the ear cavity. A method for detecting cisplatin in the ear cavity is to extract the sample from the ear cavity and, for example, by high performance liquid chromatography (HPLC) or other methods known in the art, the amount of cisplatin present in the sample. Including measuring.

The methods described herein are also useful in preventing or inhibiting ototoxicity in pediatric patients who have cancer and are receiving platinum-based chemotherapy for the treatment of cancer. It has been found that pediatric patients are particularly vulnerable to ototoxicity and that prophylactic treatment of pediatric patients can reduce ototoxicity in pediatric patients. Therefore, another embodiment described herein is a method of prophylactically treating a pediatric patient who suffers from cancer and is receiving platinum-based chemotherapy containing an effective amount of STS. Treatment reduces the likelihood that pediatric patients will suffer from ototoxicity.

It has been identified that certain genetic variants increase the probability that a pediatric patient will have ototoxicity and can cause severe ototoxicity in the patient. The genes TPMT, COMT, and ABCC3 have been shown to be at increased risk of causing ototoxicity in pediatric patients. Source: Ross et al. , "Genetic variants in TPMT and COMT are assisted with hearing loss in children receiving cisplatin chemotherapy," Nat. Genet. 41: 1345-1349 (2009); Pussegoda et al. , "Replication of TPMT and ABCC3 genetic variants is highly assisted with cisplatin-induced hearing loss in children," Clin. Pharmacol. The. 94: 243-251 (2013). In addition, it is more recently that single nucleotide polymorphisms in the ACYP2 gene at locus rs1872328 have been shown to be associated with cisplatin-based ototoxicity. Source: Xu, K. et al. , "Common variants in ACYP2 influence susceptible to cisplatin-induced hearing loss," Nat. Genet. 47 (3): 263-266 (2015). Therefore, in some embodiments, pediatric patients receiving cisplatin-based chemotherapy are identified as having an increased risk of genetic variation in one or more genes of TPMT, COMT, ABCC3, and ACYP2. It has been treated with STS to reduce, prevent, suppress, or treat the probability of ototoxicity.

In some embodiments described herein, a pediatric patient has cancer and is receiving platinum-based chemotherapy. In some other embodiments, the pediatric patient is still not diagnosed with cancer but is being treated with a platinum-based chemotherapeutic agent. Platinum-based agents are expected to be removed by STS and reduce ototoxicity. Therefore, in some embodiments, platinum-based chemotherapeutic agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin. In some embodiments, the platinum-based chemotherapeutic agent is cisplatin.

The amount of platinum-based chemotherapeutic agent received by a pediatric patient is determined by the treating physician, the type of disease or cancer being treated, and the age or weight of the pediatric patient. In some embodiments, the amount of platinum-based chemotherapeutic agent (eg, cisplatin) per dosing cycle is from about 1 mg / kg to about 5 mg / kg, including each integer within the specified range. In some embodiments, the amount of platinum-based chemotherapeutic agent (eg, cisplatin) per dosing cycle is from about 10 mg / m ² to about 300 mg / m ² , 10 mg, including each integer within the specified range. / M ² to about 100 mg / m ² , or about 40 mg / m ² to about 80 mg / m ² .

Many cancers are treated with platinum-based chemotherapeutic agents in pediatric patients who may receive STS. In some aspects of the embodiments described herein, the cancer of a pediatric patient is treated with a platinum-based chemotherapeutic agent followed by STS, the cancer being localized or disseminated. In some embodiments, the cancer is a low-risk, moderate-risk, or high-risk (such as metastatic) cancer. In some embodiments, the cancer is at low or moderate risk. In some embodiments, the cancer being treated with a platinum-based chemotherapeutic agent is localized, not disseminated or metastatic. Non-limiting and exemplary cancers that can be treated with platinum-based chemotherapy and subsequent STS include germ cell tumors (eg, testicular or ovarian cancer), hepatoblastoma, medulloblastoma, neuroblastoma, and Includes osteosarcoma. In some embodiments, the pediatric patient suffers from hepatoblastoma cancer and is being treated with platinum-based chemotherapeutic agents and STS. In some embodiments, the pediatric patient suffers from low-risk or moderate-risk hepatoblastoma cancer and is being treated with platinum-based chemotherapeutic agents and STS.

In some embodiments, the STS is administered to a pediatric patient who is being treated with a platinum-based chemotherapeutic agent before, at the same time, or after administration of a platinum-based chemotherapeutic agent. In some embodiments, the STS is administered after administration of the platinum-based chemotherapeutic agent for 0 minutes or about 5 minutes to about 96 hours, including each integer of time within a specified range. In some embodiments, the STS is about 30 minutes to about 24 hours, about 1 hour to about 24 hours, about, including each integer of time within a specified range, after administration of the platinum-based chemotherapeutic agent. It is administered for 1 to about 12 hours, about 1 hour to about 8 hours, or about 4 hours to about 7 hours. In one aspect, the STS is administered approximately 6 hours after administration of the platinum-based chemotherapeutic agent.

Administration of STS can be carried out by any known method for the purpose of administration of STS. For example, STS may be administered parenterally or enterally. For parenteral administration, STS may be administered intravenously (IV), subcutaneously (SC), or intramuscularly (IM). Enteral administration includes oral, sublingual, or rectal. In one embodiment, the STS is administered intravenously.

An effective amount of STS is the amount of STS that prevents, reduces, or inhibits ototoxicity in pediatric patients receiving platinum-based chemotherapy. In some embodiments, the amount of STS administered is from about 0.5 g / m ² to about 50 g / m ² , about 1 g / m ² to about 25 g /, including each integer within the specified range. m ² or 15 g / m ² to about 25 g / m ² . In some embodiments, the amount of STS administered is about 1 g / m ² , about 2 g / m ² , about 4 g / m ² , about 6 g / m ² , about 8 g / m ² , about 10 g / m ^2. , About 15 g / m ² , about 20 g / m ² , about 25 g / m ² , about 30 g / m ² , about 40 g / m ² , or about 50 g / m ² . An effective amount of STS is administered before or after each cycle of platinum-based chemotherapy, or at the same time as each cycle.

Some additional embodiments described herein are dosing regimens for treating cancer in pediatric patients, including administration of platinum-based chemotherapeutic agents and STS. One embodiment is a dosing regimen for treating hepatoblastoma in pediatric patients, the dosing regimen of which is approximately 1 mg / kg per cycle of platinum-based chemotherapeutic agent (including each integer within the range described). Includes administration of doses of ~ about 5 mg / kg or about 10 mg / m ² ~ about 300 mg / m ² and also per cycle of platinum-based chemotherapeutic agents (including each integer within the specified range). Includes administration of about 5 g / m ² to about 25 g / m ^{2 of STS.} In one embodiment, the STS is administered for about 2 to about 6 hours after administration of the platinum-based chemotherapeutic agent. This value includes each integer within the stated range.

Measurements of ototoxicity after administration of platinum-based chemotherapeutic agents and STS should be performed after a period of time after the last treatment with platinum-based chemotherapeutic agents and STS. In some embodiments, ototoxicity measurements are at least 3 days to about 3 months, 1 week to about 3 months, 1 week to about 2 from the last treatment with platinum-based chemotherapeutic agents and STS. It is done after a period of months, or 1 to about 4 weeks. This period includes each integer within the specified time range. In one aspect, ototoxicity is measured at least 4 weeks after the last treatment with platinum-based chemotherapeutic agents and STS.

Measurements of ototoxicity after administration of platinum-based chemotherapeutic agents and STS can be performed several times after the last administration of STS and platinum-based chemotherapeutic agents, and up to several years later. Hearing test methods for measuring hearing loss are well known to those of skill in the art and are used in combination with various scales for the purpose of assessing ototoxicity. Assessing ototoxicity allows, for example, assessment of potential ototoxicity or long-term prevention of ototoxicity by STS. The assessment of ototoxicity may be calculated by one or more criteria known in the art. For example, for ototoxicity, ear ringing function index, block grading, Children's Cancer Group 1996 study scale, Boston Children's Hospital Boston scale, Chan and Chinosolumbatana (Chang and Chinese) Scale, American Speech-Language-Healing Association Criteria, Common Terminology Criteria for Advance Events Criteria Scale (CTCAE Pediatric Ototoxicity Infant), or International Infant Oncology Boston Evaluation by Society of Pediatric Oncology Boston Ototoxicity Scale), or a combination of these scales is included. Gurney, et al. , “Oncology,” J. et al. Clin. Onc. 30 (19): 2303-2306 (2012). In most cases, after completing a measurement of auditory function, it is necessary to treat with an ototoxic drug such as cisplatin or another platinum-based chemotherapeutic agent. This treatment establishes baseline measurements of auditory function that can compare potential ototoxic effects. Therefore, changes in hearing, or enhancement or reduction of ototoxicity, are calculated relative to baseline measurements prior to the patient receiving platinum-based chemotherapeutic agents and / or sodium thiosulfate.

The definition of block scale is as follows:
Deafness less than 40 dB at all frequencies with grade 0 or minimal deafness, deafness above 40 dB only at 8,000 Hz, grade 1 or mild deafness, 4,000 Hz or higher Deafness of 40 dB or more and showing grade 2 or moderate deafness, deafness of 40 dB or more at 2,000 Hz or more and showing grade 3 or remarkable deafness, or 1,000 Hz As described above, the deafness is 40 dB or more and indicates grade 4 or severe deafness.

The CTCAE scale is based on hearing at 1 kHz, 2 kHz, 3 kHz, 4 kHz, 6 kHz, and 8 kHz. Grade 1 is a threshold shift of greater than 20 dB at 8 kHz for at least one ear. Grade 2 is a threshold shift of> 20 dB above 4 kHz in at least one ear. Grade 3 is deafness sufficient to indicate therapeutic intervention involving hearing aids, with a threshold shift of greater than 20 dB above 3 kHz in at least one ear. Directed speech and language svcs; Grade 4 is an auditory sign of cochlear implants and speech and language svcs.

The definition of the Children's Cancer Group 1996 scale is as follows:
An HL loss of 40 dB or more at 6,000 Hz and / or 8,000 Hz indicates grade 1. HL losses above 25 dB at 3,000 and / or 4,000 Hz indicate grade 2. An HL loss of more than 25 dB at 2,000 Hz indicates grade 3. An HL loss of 40 dB or more at 2,000 Hz indicates grade 4. The definition of the Children's Hospital Boston scale is as follows:
Deafness of 20 dB at a frequency of less than 500 to 8,000 Hz and no functional deafness, deafness of more than 20 dB above 4,000 Hz, functional deafness, deterioration of music appreciation indicating grade 1. It is a slight deafness that may cause deafness, a deafness of more than 20 dB at 4,000 Hz or higher, a functional deafness, an educationally significant deafness showing grade 2, and a deafness of 2,000 Hz or higher. Deafness of more than 20 dB, functional deafness, severe deafness requiring a grade 3 deafness device.

The Chang and Chinosornbatana scale is defined as 20 dB or less at 1 kHz, 2 kHz and 4 kHz and exhibits normal hearing. When (1a) 40 dB or more at an arbitrary frequency of 6 to 12 kHz and (1b) more than 20 dB and less than 40 dB at 4 kHz, grades 1a and 1b are shown, respectively. When (2a) 4 kHz or more and 40 dB or more, and (2b) more than 20 dB and less than 40 dB, grades 2a and 2b are shown at frequencies below 4 kHz, respectively. If it is 40 dB or more at 2 kHz or 3 kHz or more, it indicates grade 3. When it is 40 dB or more at 1 kHz or more, it indicates grade 4.

The definition of the criteria of the American Speech-Language-Hearing Association is as follows:
(1) 20 dB or more reduction at any one frequency, (2) 10 dB or more reduction at two or more adjacent frequencies, or (3) response at three adjacent frequencies for which a response was previously obtained. Loss of. As further specified by ASHA, significant changes in hyperacusis need to be repeatedly tested and confirmed to be considered effective.

According to the definition of the International Society of Pediatric Oncology Oncology Scale, HL of 20 dB or less at all frequencies suggests normal hearing, i.e. HL of more than 20 dB (eg, HL of 25 dB or more). In the case of over 4,000 Hz SNHL (defined as, for example, 6 or 8 kHz), it suggests grade 1. In the case of HL SNHL over 20 dB at 4,000 Hz or higher, it suggests that it is grade 2. HL SNHL over 20 dB at 2,000 Hz or 3,000 Hz or higher suggests grade 3. In the case of HL over 40 dB at 2,000 Hz (eg, HL above 45 dB), the case of SNHL suggests grade 4.

The tinnitus function index is a questionnaire-based index that quantifies the severity of tinnitus symptoms. Henry JA et al. , Audiology Today 26 (6): 40-48 (2014). The definition of the index is as follows:
An average score of 14 (range 0-17) indicates no tinnitus, and an average score of 21 suggests a low level of tinnitus. The average score of 42 is moderate tinnitus. An average score of 65 is a high level of tinnitus and an average score of 78 is a high level of tinnitus. According to the range classification, the following: Less than 25 is relatively mild tinnitus or no tinnitus. 25-50 indicate that there is a significant problem with tinnitus. More than 50 may indicate a level of tinnitus that requires active intervention.

In some embodiments, ototoxicity measures deafness at one or more frequencies, including 500 Hz, 1,000 Hz, 2,000 Hz, 4,000 Hz, or 8,000 Hz, or a combination of those frequencies. Measured by. Hearing changes are then calculated compared to baseline measurements prior to the patient receiving platinum-based chemotherapy and / or sodium thiosulfate. In some embodiments, the enhancement in ototoxicity is a loss of hearing measured by a loss of 20 dB at a single frequency, a loss of hearing measured by a loss of 10 dB at two consecutive frequencies, or a previously reresponsiveness. May be determined as loss of response at the three consecutive test frequencies obtained. In some further embodiments, the enhancement of auditory toxicity is measured as a decrease in high frequency hearing on both sides, which is a deafness of less than 40 dB at all frequencies, indicating grade 0 or minimal deafness. , Deafness of 40 dB or more at 8,000 Hz alone and showing grade 1 or mild deafness, and deafness of 40 dB or more at 4,000 Hz or higher and showing grade 2 or moderate deafness. Deafness of 40 dB or more at 2,000 Hz or higher and showing grade 3 or marked deafness, or deafness of 40 dB or more at 1,000 Hz or higher and showing grade 4 or severe deafness. It is a feature. In some further embodiments, the enhancement of ototoxicity is measured as a decrease in hearing, the characteristics of which are as follows: Deafness of 20 dB or less at all frequencies indicates grade 0 deafness. A grade 1 deafness is indicated when the HL is more than 20 dB at more than 4,000 Hz. At 4,000 Hz or higher and above 20 dB HL, grade 2 deafness is indicated. At 2,000 Hz or 3,000 Hz and above 20 dB HL, grade 3 deafness is indicated. Alternatively, in the case of HL over 40 dB at 2,000 Hz or higher, grade 4 deafness is indicated. In some other embodiments, the enhancement of ototoxicity may be measured by a reduction in the tinnitus function index.

It has been found that administration of STS to pediatric patients treated with platinum-based chemotherapeutic agents does not exacerbate kidney or other toxicity. Therefore, in some embodiments, patients receiving STS do not experience a higher severity or increased incidence of adverse events compared to patients not receiving STS. .. These adverse events include grade 3 or grade 4 neutropenia, decreased glomerular filtration rate, increased serum creatinine, infections, hypomagnesium, hypernatremia, vomiting, or nausea. Is done. In some other embodiments, pediatric patients receiving STS do not have reduced progression-free survival or overall survival compared to patients not receiving STS.

The methods described herein are highly suitable for reducing or preventing ototoxicity or reducing the probability of suffering ototoxicity in any pediatric patient of any age. Therefore, in some embodiments, the pediatric patient being treated according to the methods described herein is a newborn, or the pediatric patient is about 1 month old, about 2 months old, about 3 months old, about. 4 months old, about 5 months old, about 6 months old, about 7 months old, about 8 months old, about 9 months old, about 10 months old, about 11 months old, about 12 months old, about 1 year old, about 1 year old .5 years old, about 2 years old, about 2.5 years old, about 3 years old, about 3.5 years old, about 4 years old, about 4.5 years old, about 5 years old, about 5.5 years old, about 6 years old, about 6 years old .5 years old, about 7 years old, about 7.5 years old, about 8 years old, about 8.5 years old, about 9 years old, about 9.5 years old, about 10 years old, about 10.5 years old, about 11 years old, about 11 years old .5 years old, about 12 years old, about 12.5 years old, about 13 years old, about 13.5 years old, about 14 years old, about 14.5 years old, about 15 years old, about 15.5 years old, about 16 years old, about 16 years old .5 years old, about 17 years old, about 17.5 years old, about 18 years old, about 18.5 years old, about 19 years old, about 19.5 years old, about 20 years old, about 20.5 years old, or about 21 years old Whether to get or not is described. In some embodiments, the pediatric patient is about 12 years or younger, about 5 years or younger, about 2 years or younger, or about 1 year old or younger.

Indications and Usage In one embodiment, the sodium thiosulfate for injection described herein is induced by cisplatin (CIS) chemotherapy in patients aged 1 month to <18 years with localized non-metastatic solid tumors. It is indicated for the prevention of ototoxicity.

In one embodiment, the injectable sodium thiosulfate described herein is administered by injecting for 15 minutes 6 hours after the completion of each CIS administration, if the CIS is infused within 6 hours. In one aspect, the recommended dose of sodium thiosulfate for injection described herein for the prevention of CIS-induced ototoxicity is body weight-based and normalized to body surface area as shown below. There is.

Dosage Form and Strength The sodium thiosulfate for injection described herein is a sterile solution containing 80 mg / mL (8 g / 100 mL) of sodium thiosulfate for intravenous (IV) administration in a single-use vial.

The sodium thiosulfate for injection described herein is administered by injecting for 15 minutes 6 hours after the completion of each CIS administration, if CIS is infused within 6 hours. Pretreatment with antiemetics is recommended to reduce the incidence of nausea and vomiting.

The reason why the timing of sodium thiosulfate for injection compared to CIS chemotherapy is important is that early treatment may reduce the effectiveness of CIS and late treatment may prevent ototoxicity. This is because the effect may not be excellent.

Sodium thiosulfate for injection should be administered only after injecting CIS for 1-6 hours. Do not use sodium thiosulfate for injection if the CIS infusion exceeds 6 hours or if subsequent CIS infusions are planned within 6 hours.

Contraindications The sodium thiosulfate for injection described herein is used in patients with known hypersensitivity to either sodium thiosulfate (STS) or an inactive source of sodium thiosulfate for injection, as well as in hypernatremia. Contraindicated in newborns less than 1 month due to risk.

Description Anhydrous sodium thiosulfate, which is an active raw material, is an inorganic salt having the properties of a reducing agent. It is a white to off-white crystalline solid that is soluble in water but insoluble in alcohol. The aqueous solution is substantially neutral and has a pH in the range of 6.5-9.0. The molecular formula is Na ₂ S ₂ O ₃ . The molecular weight is 158.11 g / mol. The structural formula is as follows:

The sodium thiosulfate for injection described herein is a sterile, preservative-free, clear solution for use in intravenous injection. Each vial contains 80 mg / mL anhydrous sodium thiosulfate (US Pharmacopeia, USP), water for injection (USP), sodium borate or sodium phosphate as a buffer component, and sodium hydroxide and / or hydrochloric acid for pH adjustment. Is contained.

Mechanism of action Cisplatin-induced ototoxicity is due to irreversible damage to cochlear hair cells. Cochlea is extremely sensitive to oxidative stress and has been shown to be involved in CIS-induced deafness. The mechanism of STS protection against ototoxicity is not fully understood, but may include enhanced endogenous antioxidant levels, reactive oxygen species removal, and direct interactions between CIS and STS thiol groups. can. STS has the ability to enter the cell at least somewhat via the sodium sulfate cotransporter 2 and has intracellular effects such as enhanced antioxidant glutathione levels and inhibition of intracellular oxidative stress. It may cause it.

Pharmacodynamics STS prevented ototoxicity at doses corresponding to 6.4 to 12.8 g / m ^{2 of sodium thiosulfate for injection.} In a preliminary clinical study, ^{lowering the STS dose level (corresponding to 5.1 g / m 2} sodium thiosulfate for injection) resulted in lower maximum plasma levels (3.9 mM) but hearing protection. Was not allowed.

Delaying STS treatment for 6 hours after CIS chemotherapy is important to avoid potential interference of CIS with antitumor activity. This is supported by data from non-clinical and preliminary clinical trials. During CIS infusion, bioactive unbound CIS is dispersed in cancer cells and removed by rapid binding to renal excretion and proteins, inactivating tumor-killing activity. The initial decrease in unbound platinum in plasma is rapid, with a half-life in the range of 0.6-1.35 hours. Given the fact that most of the STS distribution is confined to the extracellular space, administration of sodium thiosulfate for injection 6 hours after each CIS injection should prevent the tumor protective effect of STS. be. As revealed in the studies, treatment 6 hours after completion of each CIS infusion had no effect on survival.

Based on the half-life of STS in plasma, the remaining amount is negligible 6 hours after the completion of STS infusion. Therefore, to avoid pharmacodynamic interactions, subsequent CIS injections should be administered within 6 hours after the completion of sodium thiosulfate injection.

A 12.8 g / m ² dose of sodium thiosulfate for injection provides a sodium load of ^{162 mmol / m 2.} Equivalent STS doses temporarily increased serum sodium levels slightly. When assessed using non-compartmental pharmacokinetic analysis in sodium thiosulfate recommended for injectable dose levels, this transient sodium increase is age, body surface area, body weight, total daily STS dose, or CIS. It had nothing to do with the cycle.

Pharmacokinetic absorption STS is poorly absorbed after oral administration and needs to be administered intravenously. At the end of intravenous injection of STS, plasma levels of STS peak and then drop rapidly, with a half-life of about 20-50 minutes. Return to pre-dose levels occurs within 3-6 hours after injection. Over 95% of urinary STS excretion occurs within the first 4 hours after administration. When STS was administered for 2 consecutive days, there was no plasma accumulation.

In infants and adults, the maximum STS plasma level after 15 minutes of injection of a dose equivalent to 12.8 g ^{/ m 2 sodium thiosulfate for injection was about 13.3 mM.} STS plasma levels vary in proportion to dose. It did not appear to affect aging, maximal plasma levels of STS or continued decline. Prediction at end of infusion with overall sodium thiosulfate recommended for injection dose levels in the indicated age and body weight range, as revealed by a population pharmacokinetic model incorporating growth and maturation variables of the pediatric population STS plasma levels were consistent.

Distribution STS does not bind to human plasma proteins. STS is an inorganic salt, and thiosulfate anions do not easily pass through the membrane. Therefore, the volume of distribution seems to be mainly limited to the extracellular space, and is estimated to be 0.23 L / kg in adults. In animals, STS has been found to be distributed in the cochlea. The distribution across the blood-brain barrier or placenta appears to be absent or restricted. Thiosulfate is an endogenous compound that is ubiquitous in all cells and organs. In adult volunteers, endogenous serum thiosulfate levels were 5.5 ± 1.8 μM.

Elimination metabolism:
Metabolites of STS have not been identified as part of clinical studies. Thiosulfate is an endogenous intermediate product of sulfur-containing amino acid metabolism. CYP enzyme is not involved in thiosulfate metabolism and is metabolized to sulfate via thiosulfate sulfur transferase and thiosulfate reductase activity, and sulfate is rapidly oxidized to sulfate.

excretion:
STS (thiosulfate) is excreted by glomerular filtration. After administration, urinary STS (thiosulfate) levels are high, about half of the STS dose is recovered unchanged in the urine, and almost all is excreted within the first 4 hours after administration. STS renal clearance was well associated with inulin clearance as a measure of GFR.

Excretion of endogenously produced thiosulfate in bile was extremely low and did not increase after STS administration. Although mass balance studies have not been conducted, non-renal clearance is expected to result primarily in renal excretion of sulfates. A small portion of STS sulfan sulfur can be part of endogenous cellular sulfur metabolism.

Pharmaceuticals, as well as storage and handling Sodium thiosulfate for injection is supplied in flint glass vials with a 20 mm stopper as 100 mL of a clear, colorless sterile solution contained in an aluminum overseal coating. Each 100 mL of sodium thiosulfate for injection contains anhydrous sodium thiosulfate (80 mg / mL) for intravenous administration (STS 8 g per vial).

Sodium thiosulfate for injection should be stored at a controlled room temperature between 15 ° C and 30 ° C.

As will be apparent to those skilled in the art of the art, without departing from the scope of any embodiment or embodiment thereof, according to the compositions, formulations, methods, processes, reactions, and applications described herein. It can be adapted by making appropriate modifications. The compositions and methods provided are exemplary and are not intended to limit the scope of any of the specified embodiments. All of the various embodiments, embodiments, and options disclosed herein may be combined in any modification or iteration. The scope of the compositions, formulations, methods, and processes described herein includes all actual or potential combinations of embodiments, embodiments, options, examples, and preferences described herein. Will be done. The exemplary constituents and formulations described herein omit any ingredients and replace them with any of the ingredients disclosed herein, or are disclosed elsewhere herein. Can contain any ingredient that is present. The ratio of the mass of any component of any of the compositions or formulations disclosed herein to the mass of other components in the formulation or the total mass of the other components in the formulation is as if the mass. Is disclosed herein as if it were explicitly disclosed. If the meaning of any term in a patent or publication incorporated by reference conflicts with the meaning of the term used in this disclosure, the meaning of the term or phrase in this disclosure shall prevail. It shall be. Furthermore, the aforementioned discussions exclusively disclose and explain exemplary embodiments. All patents and publications cited herein are incorporated herein by reference with respect to that particular teaching.

Example 1
Synthesis process The outline of the synthesis process is as shown in FIG. As shown in Scheme I, the synthesis of sodium thiosulfate (wet) is carried out with 1.0 molar equivalent of aqueous sodium sulfite in the presence of 0.00013 molar equivalent of cetylpyridinium chloride (CPC), 1.1 mol. This was achieved by reacting with an equivalent amount of elemental sulfur at 90 ° C. for up to 3 hours.

In some examples, the reaction was heated to about 90 ° C and completed when it reached 90 ° C. Without being bound by theory, the reaction rate appears to be dependent on sulfur size, surface area, and solubility (eg, fine powders are faster than flakes). Once the reaction was complete, the mixture was cooled to 25 ° C., filtered through a 10 μm filter and transferred to a crystallized vessel. The sodium thiosulfate solution was then cooled to less than 2 ° C., while maintaining a temperature below 2 ° C., slowly adding acetone over at least 1 hour, except during the first nucleation where a fever of 5-7 ° C was observed. Was added. Subsequently, the slurry was held at less than 2 ° C. for at least 0.5 hours and gradually transferred to a filter dryer in stages. After each portion of the slurry was added, the slurry was filtered to the point where the filtrate fell just below the level of the cake. This process minimized cracks in the resulting cake. The cake was then washed twice with acetone and filtered until no liquid was drained. The resulting "wet sodium thiosulfate" cake was then dried overnight at 45 ° C. while mixing under vacuum. As used herein, the term "sodium thiosulfate" refers to non-dehydrated sodium thiosulfate.

Crystallized vessels were filled with dehydrated and filtered methanol and heated to 60 ° C. The warm methanol was then transferred to a filter dryer containing a "wet sodium thiosulfate" cake that had been dried overnight. The cake was slurried with hot methanol and the filtrate was removed by pressure. A second charge of hot methanol was added, mixed and the filtrate was removed. Then, it was washed twice more with methanol at an ambient temperature, and vacuum dried at 55 ° C. overnight. This process produced anhydrous sodium thiosulfate.

Example 2
Using pulverized jet mill, d ₅₀ of the several batches of anhydrous sodium _thiosulfate, that is, 50% and the particle size distribution of the population, but was pulverized so that 10 to 20 [mu] m. The particle size distribution of unmilled anhydrous sodium thiosulfate synthesized as described herein is 50-75 μm. Without being bound by any theory, pulverization was thought to increase the surface area of the sodium thiosulfate particles and promote the evaporation of the residual solvent.

Example 3
Analysis Dry and / or ground anhydrous sodium thiosulfate was collected stored at ambient temperature. Sample analysis uses HPLC, inductively coupled plasma mass spectrometry (ICP-MS), FTIR spectroscopy, and X-ray powder diffraction to levels of sodium sulfite, sulfur, acetone, and methanol, among other trace elements. I went about. The specifications and representative data of anhydrous sodium thiosulfate synthesized as described using the method described above are as shown in Table 4.

Example 4
Characteristic Evaluation of X-ray Powder Diffraction Samples of anhydrous sodium thiosulfate or sodium thiosulfate pentahydrate described herein were analyzed by X-ray powder diffraction (XRPD). Samples 2-50 mg were placed in a zero background holder coated with a thin layer of petrolatum and flattened with a glass plate. XRPD data were obtained using a Bruker D8 X-ray diffractometer from 2 ° to 40 ° 2θ and copper Kα radiation (40 kV) at a step size of 0.05 ° (1 sec / step). During acquisition, the sample was rotated at 15 RPM. Peak picking was performed with Materials Data Jade 9.7.0 software.

The XRPD pattern of anhydrous sodium thiosulfate or sodium thiosulfate pentahydrate is as shown in FIGS. 2A and 2B, respectively. The peaks of XRPD are as shown in Tables 5 and 6, respectively. Significant peaks are shown in bold. The overlays of the anhydrous sodium thiosulfate pattern of 2A (bottom pattern) and the sodium thiosulfate pentahydrate pattern of 2B (top pattern) are as shown in FIG.

Example 4
Sodium thiosulfate binding ability assay A high performance liquid chromatography ultraviolet spectroscopy (HPLC-UV) assay was developed with the aim of quantifying the binding ability of thiosulfate to cisplatin. The method makes it possible to compare the binding abilities of different lots of sodium thiosulfate or pharmaceutical compositions containing sodium thiosulfate. The HPLC-UV method directly measures the decrease in cisplatin over time in the presence of various concentrations of sodium thiosulfate.

The method uses a Waters Accuracy H-class HPLC system equipped with an Imtake Scherzo SW-C18 mixed mode column. The outline of the conditions of the HPLC method is as shown in Table 7. The linear response of the method covers cisplatin concentrations covered by 3.3 μM (0.001 mg / mL) to 666 μM (0.2 mg / mL). This range covers more than two orders of magnitude in dose-related concentrations.

Assay by mixing an equal amount containing 333 μM, 400 μM, or 666 μM sodium thiosulfate with 666 μM cisplatin (5: 1, 6: 1, or 10: 1 thiosulfate: cisplatin ratio, respectively). carried out. Each sample was transferred to an HPLC vial and placed in an autosampler chamber maintained at 24 ° C. Samples were injected into the HPLC system approximately every 30 minutes to obtain four time points for each sample. Gradients were run and retention time and peak area were obtained. The decrease in cisplatin concentration is monitored over time to determine the half-life (time to reach 333/2 μM cisplatin based on the slope of the line) calculated as the reaction rate (eg, slope of the line, [cisplatin] / min). obtain. The control sample contained 333 μM cisplatin.

Illustrative results are as summarized in Table 8 and FIG.

Example 5
Preparation of Formulation The preparation process of the sodium thiosulfate preparation for injection is as shown in FIG. Anhydrous sodium thiosulfate was dissolved in sodium phosphate buffer (about 10 mM sodium phosphate). An exemplary sodium thiosulfate pharmaceutical formulation is shown in Table 9. The pH was adjusted to about 6.5 with NaOH and HCl or phosphoric acid. This solution was filtered twice with a 0.22 μm filter. The filtered solution was filled in a glass vial. The vial was sealed with septum and crimped. Sealed filled vials were autoclaved at 121 ° C., 15 psi for at least 0.5 hours to sterilize the contents. Vials were inspected, labeled and stored at ambient temperature.

Example 6
The steps involved in the process for producing anhydrous sodium thiosulfate described herein are as follows:
Step 1: Chemical synthesis of aqueous sodium thiosulfate,
Step 2: Crystallize sodium thiosulfate (wet) and wash with acetone,
Step 3: Dehydration and separation of anhydrous sodium thiosulfate,
Step 4: Packaging.

The synthetic pathway is as illustrated in Scheme II. Each step is as detailed below.

Synthesis of Sodium Thiosulfate In the presence of a catalytic amount of cetylpyridinium chloride (0.00013 mol equivalent), 1.0 mol equivalent of aqueous sodium sulfite is added to 1.1 mol equivalent solid element under aqueous conditions at 95 ± 5 ° C. The synthesis of aqueous sodium thiosulfate was achieved by reacting with sulfur (trace metal) to form sodium thiosulfate. See Chemical Formula II.
After 6 hours, the completeness of the reaction was verified by measuring the amount of residual sodium sulfite present (eg, by HPLC-CAD, less than 0.15% w / w sulfite). The finished reaction was then cooled to 20 ± 5 ° C. for at least 3 hours and held at 20 ± 5 ° C. for at least 1 hour. The product solution was passed through a 1 μm bag filter and then through a 0.45 μm cartridge polishing filter to remove all residual sulfur while transferring the product to a crystallization vessel.

Crystallization of sodium thiosulfate (wet) The product solution was cooled to 0 ± 5 ° C. with vigorous stirring in the crystallization vessel, about 35% of total acetone was added and at least maintained at a temperature below 10 ° C. It was mixed for 20 minutes. After incubating at 0 ± 5 ° C. for about 5 to about 20 minutes, sodium thiosulfate seed crystals were added, and crystallization was performed at 0 ± 5 ° C. for about 5 to about 20 minutes. The remaining amount of acetone was added while maintaining the temperature at 0 ± 5 ° C. Subsequently, the slurry was held at 0 ± 5 ° C. for at least 0.5 hours and then transferred to a filter dryer. The filtrate was removed by pressure filtration. After each portion of the slurry was added, the slurry was filtered to the point where the filtrate fell just below the level of the cake. This process minimized cracks in the resulting cake. Then, the cake was washed twice with acetone, sprayed with N ₂ gas until the liquid is no longer discharged. Then, obtained as a result cake "wet sodium thiosulfate", dried at ambient temperature and atmospheric pressure, was blown at least 1 hour with N ₂ cake. As used herein, the terms "wet sodium thiosulfate" or "sodium thiosulfate (wet)" refer to undehydrated sodium thiosulfate.

Dehydration and Separation of Anhydrous Sodium Thiosulfate Filtered methanol heated to 60 ± 5 ° C. is placed in a filter dryer containing a dry “wet” sodium thiosulfate material and placed at 45 ± 5 ° C. for at least 3 consecutive hours. Stirred. The material was sprayed with nitrogen for at least 2 hours. The temperature was then raised to 55 ± 5 ° C. and the solid was dried under vacuum for at least 24 hours. The residual solvent was then tested for volatile impurities using gas chromatography. The anhydrous sodium thiosulfate material was cooled to 20 ± 5 ° C. under a slight nitrogen pressure.

Immediately after cooling, the anhydrous sodium thiosulfate drug substance was transferred to an anhydrous HDPE drum. The HDPE drum was doubly lined with the LDPE bag and the desiccant was carried by the LDPE liner. Drums were purged with nitrogen gas before sealing.

The manufacturing specifications are as shown in Table 10.

The production specifications of anhydrous sodium thiosulfate produced in batches of 10 kg and 30 kg by the above method are as shown on the next page (Tables 11 and 12).

Example 7
Anhydrous sodium thiosulfate synthesized as described herein is a crystalline material that exhibits acute-angled XRPD peaks (FIG. 2A) and birefringent particles with blade and plate-like crystalline morphology. Thermal analysis by differential scanning calorimetry (DSC) revealed that a rapid single endotherm begins at the apparent melting temperature of 331.4 ° C (FIG. 4A). In thermogravimetric analysis (TGA), the weight loss at 162 ° C. from the ambient temperature was negligible. There was a 14.81% weight loss from 162 ° C to 309 ° C, after which decomposition was initiated at 436 ° C (FIG. 4A). Minimal weight changes were observed in the dynamic vapor sorption (DVS) isotherms when equilibrated to 0% relative humidity (FIG. 4B). When settled, a 165% weight increase is seen. Upon desorption, hysteresis was observed and a 51% weight loss was observed.

By comparison, as revealed by the DSC thermogram of sodium thiosulfate pentahydrate, multiple endothermic events peaked at 56 ° C, 111 ° C, 131 ° C and 141 ° C and melted at 331 ° C. Started. In TGA, a weight loss of 45.33% was observed from 25 ° C. to about 300 ° C., followed by decomposition at 456 ° C. The DVS isotherm showed a weight loss of 27% when dry. This material had a weight increase rate of 81% at the time of sorption. Upon desorption, hysteresis was observed and a 51% weight loss was observed.

Example 8
The process of preparing the sodium thiosulfate preparation is as shown in FIG. Anhydrous sodium thiosulfate was dissolved in boric acid buffer (and 4 mM boric acid). An exemplary sodium thiosulfate pharmaceutical formulation is shown in Table 13. The pH was adjusted to about 8.6-8.8 with NaOH and HCl. This solution was filtered twice with a 0.22 μm filter. The filtered solution was filled in a glass vial. The vial was sealed with a septum and an aluminum ring and crimped. Sealed filled vials were autoclaved at 121 ° C., 15 psi for at least 0.5 hours to sterilize the contents. Vials were inspected, labeled and stored at ambient temperature.

The manufacturing specifications of the sodium thiosulfate preparation for injection are as shown in Table 14.

Example 9
Exemplary sodium thiosulfate pharmaceutical formulations are as shown in Tables 15-23. These formulations are prepared as described herein.

Claims (50)

A pharmaceutical composition comprising aqueous anhydrous sodium thiosulfate, one or more buffers, and a solvent. The composition according to claim 1, wherein the composition comprises from about 20 mg / mL to 320 mg / mL aqueous anhydrous sodium thiosulfate. The composition according to claim 1 or 2, wherein the composition contains from about 8% by mass to about 32% by mass of aqueous anhydrous sodium thiosulfate. The composition according to any one of claims 1 to 3, wherein the composition comprises about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate. The composition according to any one of claims 1 to 4, wherein the composition comprises one or more buffers of about 0.001 M to about 0.5 M. One or more of the above buffers are phosphate, borate, sulfate, carbonate, formate, acetate, propionate, butanoate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, α-ketoglutarate, succinate, fumarate, malate, The composition according to any one of claims 1 to 5, which comprises oxaloacetate, aspartate, glutamate, tris (hydroxymethyl) aminomethane (tromethamine), a combination thereof, or a salt thereof. The composition according to any one of claims 1 to 6, wherein the composition has a pH of about 5 to about 9.5. The composition according to any one of claims 1 to 7, wherein the composition has a pH of about 6.5 or about 8.9. Any one of claims 1 to 8, wherein the one or more buffers contain borate or a salt thereof, glycine or a salt thereof, tris (hydroxymethyl) aminomethane (tromethamine) or a salt thereof, or phosphate or a salt thereof. The composition according to. The composition according to any one of claims 1 to 9, wherein the one or more buffers contain boric acid, glycine, tris (hydroxymethyl) aminomethane (tromethamine), or sodium phosphate. The composition according to any one of claims 1 to 10, wherein the solvent contains water. The composition according to any one of claims 1 to 11, wherein the composition is sterile. A pharmaceutical composition comprising from about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate, 0.001 M to about 0.5 M sodium phosphate, boric acid, glycine, or tris (hydroxymethyl) aminomethane (tromethamine). The composition according to claim 13, wherein the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M sodium phosphate having a pH of 6.5. The composition according to claim 13 or 14, wherein the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.004 M borate or a salt thereof having a pH of 8.6 to 8.8. 13. The composition according to one item. The composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M tris (hydroxymethyl) aminomethane (tromethamine) at pH 8.5-8.9 or a salt thereof. The composition according to any one of claims 13 to 16, which comprises. A pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate having a pH of 6.5, and water. A pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M borate or a salt thereof having a pH of 8.6 to 8.8, and water. A pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine or a salt thereof at pH 8.5-8.9, and water. Includes about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M tris (hydroxymethyl) aminomethane (tromethamine) at pH 8.5-8.9 or a salt thereof, and water. Pharmaceutical composition. A method for preparing a pharmaceutical preparation containing anhydrous sodium thiosulfate, which comprises combining anhydrous sodium sulfate with one or more buffers and solvents. 22. The method of claim 22, further comprising filtering and sterilizing the formulation. The method of claim 22 or 23, wherein the formulation comprises from about 20 mg / mL to 320 mg / mL aqueous anhydrous sodium thiosulfate. The method according to any one of claims 22 to 24, wherein the formulation comprises from about 8% to about 32% by weight aqueous anhydrous sodium thiosulfate. The method according to any one of claims 22 to 25, wherein the formulation comprises from about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate. The method according to any one of claims 22 to 26, wherein the formulation comprises one or more buffers of about 0.001 M to about 0.5 M. One or more of the above buffers are phosphate, borate, sulfate, carbonate, formate, acetate, propionate, butanoate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, α-ketoglutarate, succinate, fumarate, malate, The method according to any one of claims 22 to 27, which comprises oxaloacetate, aspartate, glutamate, tris (hydroxymethyl) aminomethane (tromethamine), a combination thereof, or a salt thereof. The method according to any one of claims 22 to 28, wherein the preparation has a pH of about 5 to about 9.5. The method according to any one of claims 22 to 29, wherein the formulation has a pH of about 6.5 or about 8.9. Any one of claims 22-30, wherein the one or more buffers comprises glycine or a salt thereof, borate or a salt thereof, tris (hydroxymethyl) aminomethane (tromethamine) or a salt thereof, or phosphate or a salt thereof. The method described in. The method of any one of claims 22-31, wherein the one or more buffers comprises sodium phosphate, glycine, tris (hydroxymethyl) aminomethane (tromethamine), or boric acid. The method according to any one of claims 22 to 32, wherein the solvent comprises water. The method according to any one of claims 22 to 33, wherein the preparation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate having a pH of 6.5, and water. 22 to 33, wherein the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid at pH 8.6 to 8.9, and water. the method of. Any of claims 22 to 33, wherein the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine at pH 8.5-8.9, and water. The method described in paragraph 1. The formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M tris (hydroxymethyl) aminomethane (tromethamine) at pH 8.5-8.9, and water. , The method according to any one of claims 22 to 33. The pharmaceutical preparation produced by the method according to claim 22, which comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate having a pH of 6.5, and water. A pharmaceutical preparation produced by the method according to claim 22, which comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid having a pH of 8.6 to 8.8, and water. It is produced by the method according to claim 22, which comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine having a pH of 8.5 to 8.9, and water. Pharmaceutical product. 22. A water-based anhydrous sodium thiosulfate of about 0.5 M, tris (hydroxymethyl) aminomethane (tromethamine) having a pH of 8.5 to 8.9 and about 0.01 M to about 0.05 M, and water. A pharmaceutical preparation produced by the method described in 1. A means for preparing a pharmaceutical preparation containing anhydrous sodium thiosulfate, which comprises combining anhydrous sodium sulfate with one or more buffers and a solvent. A preparation prepared by the means according to claim 42. A sterile aqueous solution of about 0.2M to about 2M sodium thiosulfate, a pharmaceutically acceptable buffer of about 0.001M to about 0.05M, and a pharmaceutically acceptable solution of about 0.005M to about 0.05M. A pharmaceutical composition containing sodium thiosulfate at a pH of about 5 to about 9.5. A kit comprising a sterile aqueous sodium thiosulfate preparation comprising one or more receptacles containing aqueous sodium thiosulfate and a document containing prescription information or instructions for use. The kit of claim 45, further comprising one or more syringes, a subcutaneous injection needle, and packaging. Includes one or more receptacles containing dried or lyophilized sodium thiosulfate, optionally one or more sterile solvents suitable for reconstruction, needles and syringes, and prescription information or instructions for use. A kit that includes the documents that are available. A pharmaceutical formulation containing stable aqueous anhydrous sodium thiosulfate for injection that does not precipitate after sterilization and storage. The formulation comprises from about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate, 0.001 M to about 0.5 M sodium phosphate, glycine, tris (hydroxymethyl) aminomethane (tromethamine), or boric acid. The pharmaceutical formulation according to claim 48. A method for preventing or reducing the incidence of cisplatin (CIS) chemotherapy-induced ototoxicity in patients with localized non-metastatic solid tumors aged 1 month to <18 years, injecting CIS for up to 6 hours. If so, a method comprising administering sodium thiosulfate for injection as an injectate for 15 minutes approximately 6 hours after the completion of administration of each CIS.

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